@article {pmid40553395,
year = {2025},
author = {Xu, Z and Zhu, Y and Liu, L and Liu, C and Zhang, Z and Li, M and Yao, L and Wang, F and Dong, Z and Gao, S and Kang, L and Shi, L},
title = {An analysis of the therapeutic efficacy and underlying mechanisms of combining lycopene with dental pulp stem cells to ameliorate alzheimer's disease in rats.},
journal = {Metabolic brain disease},
volume = {40},
number = {6},
pages = {233},
doi = {10.1007/s11011-025-01661-3},
pmid = {40553395},
issn = {1573-7365},
abstract = {The choroid plexus (CP), which is responsible for forming the blood-cerebrospinal fluid barrier, contributes to the modulation of deficits in Alzheimer’s disease (AD) by enhancing neuroinflammatory and brain immune responses. Previous research has demonstrated that lycopene (LYCO) or dental pulp stem cells (DPSCs) can attenuate AD-related inflammatory responses. However, it remains unclear whether LYCO and DPSCs can synergistically ameliorate neuroinflammation in the CP. Therefore, this study aims to investigate the feasibility of combining LYCO with DPSCs to mediate immunomodulatory effects within the CP in a rat model of AD. The findings indicated that oral administration of LYCO, transplantation of DPSCs, and the combination of these two methods significantly enhanced the learning and memory capabilities of AD rats in the water maze test, including improvements in directional sense and spatial orientation abilities. Furthermore, these treatments were associated with a reduction in pro-inflammatory mediators (TNF-α and IL-1β) and an increase in anti-inflammatory mediators (IL-10 and TGF-β1) within cerebrospinal fluid and hippocampal tissue. Furthermore, treatment with LYCO, DPSCs, or their combination effectively reverses Aβ1−42-induced upregulation of Toll-like receptor 4 expression at both mRNA and protein levels, as well as the expression of NF-κB p65. This study presents novel experimental evidence supporting the combined therapeutic potential of LYCO and DPSCs in modulating immune responses within the CP, while also offering valuable insights into the pathophysiology of AD and potential mechanisms associated with CP.},
}

@article {pmid40571874,
year = {2025},
author = {Qadir, H and Hussain, SH and Ghaffar, A and Shah, FA and Ahmed, S},
title = {Targeting Fyn Kinase for Alleviation of Cognitive Impairment in Streptozocin-Induced Alzheimer's Disease in Mice by Loperamide; An Experimental and in Silico Analysis.},
journal = {Neurochemical research},
volume = {50},
number = {4},
pages = {212},
pmid = {40571874},
issn = {1573-6903},
abstract = {Alzheimer’s disease (AD) is a complex, progressive neurodegenerative disorder that leads to irreversible deterioration of neuronal cells over time. It is the most frequent cause of dementia in elderly individuals globally. Current treatment drugs exhibit modest effect on AD patients. Fyn kinase is implicated in AD pathogenesis, and its interactions with both AD hallmarks Aβ and tau make it a unique therapeutic target. To explore small molecule inhibitors effective in treating AD, FDA-approved drugs were evaluated using molecular docking to determine their affinity for Fyn kinase. The findings of molecular simulations support the repurposing of loperamide for treating AD. Swiss albino mice were divided into six groups, including sham control, STZ group, donepezil-treated positive control, and three loperamide-treated groups with varying doses (2.5, 5, 10 mg/kg). Cognitive functions were assessed using Novel Object Recognition (NOR), Morris Water Maze (MWM), and Elevated plus Maze (EPM) tests. Histological analyses were performed using Congo red, haematoxylin-eosin, and nissl staining. Gene expression of AD markers including Fyn, App, tau, Dlg4, Gfap, Bdnf, Cal1, Ide, Nep, and Sv2a were evaluated using qPCR. For protein quantification, amyloid beta 42 levels were measured using ELISA, while tau phosphorylation was assessed by immunohistochemistry. Our results show that loperamide treatment significantly improved cognitive function in mice, reduced amyloid accumulation and neuronal loss, and enhanced Aβ clearance most probably by upregulating Nep and Ide. Additionally, qPCR results revealed a significant decrease in Fyn expression. Amyloid beta 42 levels were significantly reduced by loperamide treatment, accompanied by decreased phosphorylated tau immunoreactivity in the cortex, dentate gyrus, and cornu ammonis 1 region. We conclude from these investigations that loperamide may serve as a promising therapeutic agent for AD by potentially targeting Fyn kinase, suggesting that further research is needed to explore its effectiveness in treating AD.},
}

@article {pmid41212305,
year = {2026},
author = {Li, Z and Jia, L and Huai, S},
title = {Bidirectional causal association between cathepsins and neuropsychiatric disorders: univariate and multivariate Mendelian randomization study.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {276},
number = {4},
pages = {1775-1787},
pmid = {41212305},
issn = {1433-8491},
abstract = {BACKGROUND: Neuropsychiatric disorders are among the most common diseases worldwide and are characterized by complex pathogenic mechanisms. Cathepsins (CTS) are crucially involved in the pathogenesis and treatment of numerous diseases. Increasing evidence suggests a relationship between cathepsins and neuropsychiatric disorders. However, the causal associations remain unclear. METHODS: We performed a bidirectional two-sample Mendelian randomization (MR) analysis, applying univariable (UVMR) and multivariable MR (MVMR) to evaluate the causal association between nine cathepsins and five neuropsychiatric disorders. Data for this study were derived from genome-wide association studies (GWAS). The MR analysis primarily used five methods: Inverse Variance Weighted (IVW), Weighted Median Estimator (WME), MR-Egger regression, Simple mode, and Weighted mode. Additionally, sensitivity tests were employed to assess the robustness of the MR results. RESULTS: MR analyses indicated that CTSH is associated with an increased risk of Alzheimer’s disease (AD) (UVMR: OR, 1.041; 95% CI, 1.013–1.069; p = 0.004; MVMR: OR, 1.040; 95% CI, 1.014–1.066; p = 0.003; replication UVMR: OR, 1.046; 95% CI, 1.014–1.082; p = 0.011). Findings that were significant in only one MR approach, such as the putative causal effects of CTSF on AD and bipolar disorder (BIP), of CTSL2 on major depressive disorder (MDD), and of CTSH and CTSE on Parkinson’s disease (PD) should be interpreted with caution. CONCLUSION: CTSH can be considered a plasma biomarker for AD, offering new insights and potential directions for the prevention and treatment of AD. Additionally, during the treatment of BIP and PD, attention should be paid to CTSF and CTSE expression levels to maintain physiological homeostasis.},
}

@article {pmid41372737,
year = {2025},
author = {Shah, A and Doshi, G},
title = {Stress and neurodegeneration: mechanistic insights and therapeutic opportunities for preserving brain resilience.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {41372737},
issn = {2240-2993},
abstract = {Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis are strongly influenced by persistent stress, which accelerates both their onset and progression. This review explores the intricate interplay between chronic stressors, oxidative and metabolic imbalances, protein misfolding, inflammatory responses, and psychosocial adversity, and their cumulative impact on the aging brain’s capacity for homeostasis. The loss of cellular resilience due to prolonged stress leads to maladaptive outcomes, including mitochondrial dysfunction, sustained neuroinflammation, breakdown in proteostasis, and disruption of hypothalamic-pituitary-adrenal axis signaling, all of which amplify neuronal vulnerability. The detailed molecular pathways that underlie these phenomena, the article identifies key mediators such as Reactive Oxygen species, mitochondrial regulators, heat shock proteins, and proinflammatory cytokines that drive neurodegeneration. A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar up to 2025. Eligible publications included original research articles, clinical studies, and systematic reviews focusing on stress-related molecular pathways, oxidative metabolism, proteostasis, neuroinflammation, and therapeutic interventions in aging and neurodegenerative diseases. A qualitative synthesis of these studies was performed to identify key mechanisms, biomarkers, and emerging treatment strategies relevant to stress-induced neurodegeneration. Further, the review evaluates both established and emerging interventions aimed at mitigating these stress-driven processes. Lifestyle modifications such as aerobic exercise, calorie restriction, and cognitive behavioural therapies complement pharmacological agents like antioxidants, chaperone modulators, and anti-inflammatory drugs to enhance brain resilience and delay disease onset. Recent advances in the field, including integrated multi-omics profiling, biomarker discovery, and medicine approaches, promise to refine our ability to satisfy patients and deliver targeted therapies based on individual stress profiles. Additionally, the article discusses the neuroimmune-gut axis and the potential for interventions targeting microbiome-related inflammation. Early detection of stress-related biomarkers and personalized strategies holds considerable promise for improving clinical outcomes, enabling earlier diagnosis, and fostering tailored therapies that preserve cognitive function and independence in aging populations.},
}

@article {pmid41575555,
year = {2026},
author = {Yu, S and Ye, Z and Zhao, W and Yu, X and Qiu, Y and Lin, K and Lu, T and Ge, L and Sun, J and Hua, R},
title = {Genetic evidence on chemical communication between gut microbiota and neurological and psychiatric disorders: a Mendelian randomization study.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {276},
number = {4},
pages = {1759-1773},
pmid = {41575555},
issn = {1433-8491},
support = {2019YFC1708601//the National Key Research and Development Program of China/ ; SZ2021ZZ14//the Specific Fund of State Key Laboratory of Dampness Syndrome of Chinese Medicine/ ; YN2018ZD04and2019-140//the Guangdong Provincial Key Laboratory of Research on Emergency in traditional Chinese medicine (TCM)/ ; },
abstract = {BACKGROUND: Accumulating evidence from clinical trials and preclinical studies revealed the importance of the microbiota-gut-brain axis (MGBA) in neurological and psychiatric disorders (NPDs). MGBA remains a blueprint for extended explorations. METHODS: We examine the bidirectional association between 5 NPDs (late-onset Alzheimer’s disease (AD), migraine, autism spectrum disorder (ASD), all anxiety disorder, depression) and gut microbiota (GM) via microbial-derived metabolites, neurotransmitter, and precursors including total branched-chain amino acids (BCAA), isoleucine, leucine, valine, acetate, tryptophan, kynurenine, glutamate, tyrosine, serotonin using two step Mendelian randomization. Five methods were performed, including inverse variance weighted, MR Egger regression, weighted median, weighted mode, and simple mode. The robustness of results was supported by Cochran’s Q test, the MR-Egger regression, the MR pleiotropy residual sum and outlier, and the leave-one-out method. RESULTS: After false discovery rate correction, we found elevated isoleucine in plasma as a risk factor for AD and elevated tyrosine in plasma as a risk factor for anxiety. Conversely, AD has genetically effect on a lower level of total BCAA, isoleucine, leucine, valine, glutamate, and tyrosine in plasma. We also found that Clostridia, Clostridiales, Sutterella, and Ruminococcus torques group were positively correlated with isoleucine. Elevated Sutterella abundance was found strongly positively correlated with ASD. Desulfovibrionales and Desulfovibrionaceae were found strongly positively correlated with AD. Pathways of Clostridia/Clostridiales/Ruminococcus torques group/Sutterella- isoleucine- AD were established with mediating percentages ranging from − 54.265% to 132.908%. CONCLUSION: Our study elucidates how chemical signalling bridges communication between GM and NPDs, paving avenues for microbiota-based treatment.},
}

@article {pmid41603981,
year = {2026},
author = {Raswanthiya, SP and Fernandes, OP and Mathew, MP and Balgote, PJ and Sivaraman, J},
title = {Decoding BDNF in neurodevelopmental, neurodegenerative, and neurological disorders: mechanisms and therapeutic perspectives.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {330},
pmid = {41603981},
issn = {1573-4978},
abstract = {Brain-Derived Neurotrophic Factor (BDNF) is an essential neurotrophin involved in neuronal survival, synaptic plasticity, and neurogenesis, critical for normal brain function as well as the pathology of neurological and psychiatric disorders. It primarily functions by activating TrkB receptors, which subsequently modulate intracellular signalling pathways such as PI3K-Akt, Ras-MAPK, and PLC-γ1. The expression of BDNF is precisely controlled by genetic, epigenetic, and transcriptional mechanisms, with environmental and activity-dependent factors providing further modulation. However, it is worth noting that BDNF dysregulation has been linked to major diseases such as depression, schizophrenia, autism spectrum disorder, epilepsy, Alzheimer’s disease (AD), and Parkinson’s disease (PD), and depression, with growing evidence supporting its use as a biomarker for disease monitoring and treatment. This review provides a comprehensive overview of BDNF synthesis, regulation, and signalling mechanisms, highlighting its context-dependent roles in both health and disease. It also examines the role of BDNF in cerebellar development, specifically its effects on granule cells, Purkinje cells, and interneurons govern neuronal survival, migration, and synaptic refinement, and its disruption may predispose to neuropsychiatric vulnerability. While BDNF modulation correlates with clinical outcomes, it remains unclear whether BDNF upregulation directly contributes to therapeutic efficacy or is merely an associated response. BDNF shows promise as a diagnostic biomarker and therapeutic target, merging mechanistic and clinical insights, but requires further research for full potential in precision medicine.},
}

@article {pmid41636819,
year = {2026},
author = {Fu, H and Feng, J and Zhang, X and Tian, L and Sun, S and Bo, H and He, C and Wang, X},
title = {Memantine mitigates radiation-induced cognitive impairment by modulating AKT/GSK3β signaling.},
journal = {Radiation and environmental biophysics},
volume = {65},
number = {1},
pages = {257-269},
pmid = {41636819},
issn = {1432-2099},
support = {NO.HYZHXM02004//State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center/ ; xcxjh20230610//Foundation of the Graduate Innovation Center, Nanjing University of Aeronautics and Astronautics/ ; },
abstract = {Memantine hydrochloride (MH), primarily employed in the clinical treatment of Alzheimer’s disease (AD), has been reported to exert beneficial effects on radiation-induced cognitive impairment; however, its underlying mechanisms have not been fully elucidated. In this study, a mouse model of radiation-induced injury was established. ICR(Institute of Cancer Research) mice were divided into six groups: control, 8 Gy irradiation, prophylactic 20 mg/kg + 8 Gy, prophylactic 40 mg/kg + 8 Gy, post-irradiation 8 Gy + 20 mg/kg, and post-irradiation 8 Gy + 40 mg/kg. Behavioral assessments indicated that ionizing radiation induced spatial cognitive deficits, which were ameliorated by MH administration. Morphological analyses revealed neuronal damage, synaptic injury, and demyelination in the hippocampal dentate gyrus (DG) region, which were markedly attenuated following MH treatment. Western blot analysis demonstrated that radiation upregulated dopamine D2 receptor (D2R) and β-arrestin 2 expression, suppressed PP2A expression, promoted AKT dephosphorylation, and led to GSK3β overactivation, along with increased expression of MBP and PLP1—potential mechanisms underlying radiation-induced cognitive impairment. MH administration downregulated D2R and β-arrestin 2, enhanced PP2A-AKT interaction, reduced GSK3β activity, and upregulated MBP and PLP1 expression. Notably, prophylactic administration conferred greater neuroprotection than post-irradiation treatment. These findings provide preliminary insight into the protective mechanisms of MH against radiation-induced cognitive impairment and offer a basis for future studies in radiation neuroprotection.},
}

@article {pmid41701395,
year = {2026},
author = {Nisar, A and Akhter, N and Chauhdary, Z and Anjum, F and Saleem, F and Sana, S and Rafiq, I and Mustafa, A},
title = {Investigating the Neuroprotective Effects of Saw Palmetto Fruit Extract Against D-Galactose and Aluminum Chloride Induced Alzheimer's Disease: In Vivo Study.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {76},
pmid = {41701395},
issn = {1573-6903},
abstract = {Serenoa repens (Saw palmetto) contain 85–90% fatty acids and other constituents include sterols rich in components as carotenoids, lipases, tannin and sugars. The purpose of this study is to investigate the therapeutic potential of Saw palmetto fruit extract against Alzheimer’s disease in a mice model. Phytochemical analysis was performed by HPLC analysis after preparation of plant extract by microwave assisted extraction technique.AD induced in mice by D-galactose and aluminum chloride 100 mg/kg of each (orally), and treated with saw palmetto fruit extract 250 mg/kg, 500 mg/kg, and 800 mg/kg were administered orally for 21 days. Neurobehavioral observations were performed to determine the pharmacological manipulation on cognitive and behavioral functions. Mice were sacrificed after behavioral studies to perform biochemical, neurochemical and gene expression analysis. Neuro-active compounds detected in HPLC analysis like chlorogenic acid, p-coumaric acid, gallic acid, HB acid and salicylic acid were screened by the molecular docking and interaction analysis. SP extract treatment showed dose-dependent neuroprotective effects as manifested by neurobehavioral, histopathological analysis which showed that with 250 mg/kg moderately enhance the synaptic density and neuronal survival. Notable neurodegenerative effects were observed at 800 mg/kg, accompanied by reduced neurodegenerative histopathology at 500 mg/kg. Phytochemicals in SP extract showed most stable conformation within the active site of target protein AChE. ADMET results sustained the computational experiments by presenting significant results, further molecular dynamic analysis also confirms the perfect interaction of the target AChE protein with Quercetin, Chlorogenic acid. These five phytochemicals could be recommended for clinical testing for management of Alzheimer’s disease.},
}

@article {pmid41746530,
year = {2026},
author = {Jadhav, VP and Mohanty, PK},
title = {Neuroprotective Effects of Citropten Against Scopolamine-Induced Cognitive Impairment and Oxidative Stress in a Rat Model.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41746530},
issn = {1573-6903},
abstract = {Alzheimer’s disease (AD) is a chronic and progressive neurological degeneration marked by cognitive impairment and memory deficits, with oxidative stress and disturbances in the cholinergic system serving as key pathological factors. The current investigation sought to evaluate the neuroprotective and cognition-enhancing properties of Citropten (5,7-dimethoxycoumarin), a bioactive compound belonging to the coumarin class, in a scopolamine-induced cognitive impairment model. Wistar rats were divided into vehicle control, scopolamine alone, standard drug, and two Citropten-treated groups (12.5 and 25 mg/kg), and treated orally once daily for 18 days. Cognitive impairments were induced by daily scopolamine administration (2 mg/kg, i.p.) from Day 8 onward. Behavioral performance was analysed with the Novel Object Recognition (NOR), Elevated Plus Maze (EPM) and Morris Water Maze (MWM). Post-behavioral testing, brain tissues were analysed for acetylcholinesterase (AChE) activity, level of malondialdehyde (MDA), reduced glutathione (GSH), and catalase (CAT) activity. Scopolamine significantly impaired spatial, and recognition memory, as well as EPM-based learning memory performance, increased AChE activity and MDA levels, and reduced GSH and CAT activity compared with vehicle control group. Citropten treatment dose-dependently improved escape latency and target quadrant time spent in the MWM, enhanced the discrimination index in NOR test, and reduced transfer latency in the EPM. Biochemically, Citropten significantly reduced AChE and MDA levels while restoring GSH and CAT activity, showing effects comparable to the standard drug, Donepezil. Our findings demonstrate that Citropten exhibits multi-targeted neuroprotective agent, with potential relevance for mitigating cognitive dysfunction associated with cholinergic and oxidative stress pathways in scopolamine-induced cognitive impairment model.},
}

@article {pmid41758263,
year = {2026},
author = {Movaffagh, S and Behzadifard, M and Moghaddasi, M and Nazarinia, D and Jafaripour, L},
title = {Kinetin mitigate neurodegenerative damage of Alzheimer induced by beta-amyloid in male rats by antioxidant and antithrombotic effects.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41758263},
issn = {1573-7365},
abstract = {Alzheimer’s disease (AD) is a neurodegenerative disease that is charactrized by impaired memory and cognitive function. Kinetin (Kn) is a drug that possesses antioxidant and antithrombotic properties. This study aimed to evaluate the effects Kn as a potential treatment for AD in a rat model. Thirty-five Wistar rats were randomly divided into five groups: sham, Aβ, Aβ + 0.5 mg/kg Kn, Aβ + 1 mg/kg Kn, and 1 mg/kg Kn. Beta-amyloid was administered via bilateral intraventricular injection of 10 µl. KN was injected intraperitoneally for two weeks. Subsequently, behavioral tests were conducted, and plasma was used for the thrombolytic test. Hippocampal tissue was analyzed for oxidative stress markers, inflammatory cytokine expression, apoptosis-related gene expression, and neuronal damage. In the Aβ group, behavioral tests demonstrated impaired memory. Levels of plasminogen activator inhibitor-1 (PAI-1), malondialdehyde (MDA), the expression of tumor necrosis factor-alpha (TNF-α) and BAX genes, and the number of degenerated neurons in the hippocampus were significantly increased compared to the sham group. Conversely, glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), plasma tissue plasminogen activator (t-PA) level, and bcl-2 gene expression were significantly decreased in the Aβ group relative to sham controls. Treatment with kinetin improved memory performance and significantly reduced plasma level of PAI-1, MDA, and TNF-α, BAX expression, and neuronal degeneration. Additionally, kinetin significantly increased GSH, SOD, CAT, t-PA levels, and bcl-2 gene expression. Our study showed that kinetin, especially at a dose of 1 mg/kg, with its antioxidant and antithrombotic properties, reduces hippocampal tissue damage following Aβ-induced Alzheimer’s disease, thereby alleviating memory and learning impairments in rats.},
}

@article {pmid41831181,
year = {2026},
author = {Jankowski, WM and Fichna, J and Tarasiuk-Zawadzka, A},
title = {Can Nutrition Modulate the Progression of Alzheimer's Disease? A Narrative Review.},
journal = {Current nutrition reports},
volume = {15},
number = {1},
pages = {},
pmid = {41831181},
issn = {2161-3311},
support = {#503/1-156-04/503-11-001//Uniwersytet Medyczny w Lodzi/ ; },
abstract = {PURPOSE OF REVIEW: Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the nervous systems, along with the accumulation of abnormal proteins in brain structures. The most common neurodegenerative disease is Alzheimer’s disease (AD), which manifests as memory loss, cognitive deficits, communication difficulties, personality changes and impaired ability to perform daily activities. The purpose of this study is to gather available information on the relationship between dietary habits and the pathogenesis of AD. RECENT FINDINGS: A growing body of scientific literature points to the important influence of diet and its nutrients on the mechanisms of AD development. Polyphenols play a key role in reducing oxidative stress and inflammation in the brain. B vitamins, as well as vitamins A, C, D and E, help protect neurons and improve cognitive function. In addition, omega-3 fatty acids, inhibit the formation of amyloid beta deposits and reduce hyperphosphorylation of tau protein. It is worth noting that the Mediterranean diet has shown beneficial effects on brain health, in contrast to the Western diet, which promotes the development of these conditions. Recent studies also emphasize the role of the gut microbiota and its metabolites, such as short-chain fatty acids, as factors involved in preventing the development of AD. A balanced diet, such as the Mediterranean diet, rich in antioxidants, anti inflammatory components and supportive of a healthy gut microbiome, can slow the progression of AD and serve as a complementary approach to its treatment.},
}

@article {pmid41854817,
year = {2026},
author = {Yang, H and Fu, R and Duan, Y and Hua, Y and Wei, T and Li, G and Gu, X and Li, M and Yu, X and Li, L and Cao, L and Wang, ZZ and Zhang, C and Lv, Y and He, M and Xiao, W},
title = {Tubuloside B Alleviates Aβ25-35 Induced PC12 Cell Injury by Attenuating Pyroptosis, Apoptosis and Excessive Autophagy.},
journal = {Neurotoxicity research},
volume = {44},
number = {2},
pages = {},
pmid = {41854817},
issn = {1476-3524},
support = {2440STCZB2614//industrial foundation reengineering and high-quality development of manufacturing industry/ ; },
abstract = {Cistanche, a traditional Chinese medicine with reported neuroprotective effects, contains multiple bioactive constituents whose specific mechanisms of action remain incompletely defined. Here, we aimed to identify a key neuroprotective component and explore its potential mechanism against Aβ-induced neurotoxicity. Fourteen commercially available Cistanche-derived compounds were screened for neuroprotection in an Aβ25-35 (Aβ fragment 25–35)-injured PC12 cell model. The most active compound, Tubuloside B (TB), was further investigated using polymerase chain reaction (PCR) array, immunoblotting, flow cytometry, immunofluorescence, and mitochondrial function assays. TB exerted concentration-dependent protective effects in the Aβ25-35-injured PC12 model. Aβ25-35 exposure was associated with marked activation of pyroptotic signaling, characterized by caspase-1 activation, GSDMD cleavage, and increased interleukin (IL)-1β/IL-18 levels. These alterations were substantially blunted in the presence of TB. Modulation of the absent in melanoma 2 (AIM2) inflammasome pathway was further supported by reduced AIM2 expression and diminished apoptosis-associated speck-like protein containing a CARD (ASC) speck formation. Mitochondrial perturbations induced by Aβ25-35, including excessive mitochondrial reactive oxygen species (ROS) generation, membrane depolarization, and cytosolic mtDNA accumulation, were concurrently ameliorated by TB. In addition, markers of apoptosis and dysregulated autophagy were partially normalized following TB treatment. These findings suggest that TB may contribute to neuroprotection in an Aβ25-35-induced PC12 cell model, potentially involving modulation of mitochondrial dysfunction–associated inflammasome activation and downstream cell death pathways. Given the in vitro design and limited sample size, these results should be considered preliminary and warrant further validation in vivo.},
}

@article {pmid41863595,
year = {2026},
author = {Ji, J and Li, Z and Xing, A and Luo, G and Zhai, X and Xu, W and Li, J and Tan, T and Jia, R and Yan, Y and Zhang, X and Wang, L and Li, J and Li, K},
title = {Causal relationships between alzheimer's disease genetics and brain connectivity alterations: a multi-modal mendelian randomization study with transcriptomic validation of 191 rs-fMRI and 635 DTI neuroimaging traits.},
journal = {Brain imaging and behavior},
volume = {20},
number = {2},
pages = {},
pmid = {41863595},
issn = {1931-7565},
support = {2023XM016//Four "Batches" Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province/ ; 0033/2023/RIB2//The Science and Technology Development Funds of Macao/ ; RP/FCA-14/2023//a Grant from Macao Polytechnic University/ ; },
abstract = {Traditional observational magnetic resonance imaging (MRI) studies have revealed changes in brain connectivity in Alzheimer’s disease (AD). However, the findings have been inconsistent due to small sample sizes and potential confounding factors. The genetic effects of AD on the inherent brain activity and connectivity of patients are still not well understood. We utilized summary-level GWAS data for 223,906 Europeans from three large AD cohorts and comprehensive GWAS data for 191 rs-fMRI functional connectivity (FC) traits (n = 34,691) and 635 diffusion tensor imaging (DTI) metrics (n = 33,292) from the BIG Knowledge Portal. A bidirectional two-sample Mendelian randomization (MR) analysis with multiple MR methods was performed to evaluate the causality between AD genetics and genetically predicted whole-brain functional and structural connectivity changes. A series of sensitivity analyses were systematically conducted to assess the pleiotropy, heterogeneity, and outliers. Additionally, SNP-to-gene mapping, enrichment analysis, protein-protein interaction (PPI), single-SNP, and SNP location-based MR were performed to elucidate the molecular mechanisms. To validate our findings, we analyzed an independent cohort from ADNI (n = 30/group) and performed transcriptomic validation using RNA-seq data from 63 samples (32 AD, 31 control). Our MR analysis revealed significant causal associations between AD and specific alterations in fMRI FC, particularly involving the precuneus, occipital lobe, and default mode network. Similarly, AD was causally linked to changes in fractional anisotropy (FA) and mean diffusivity (MD) across distinct white matter fiber tracts. The molecular mechanisms underlying these MRI changes involved polygenic contributions from multiple AD-associated SNPs, primarily those mapped to non-coding regions, in addition to genic SNPs enriched in pathways regulating amyloid-beta clearance and neuroinflammation. External validation using the ADNI cohort confirmed the FC alterations identified through MR. Transcriptomic validation confirmed the significant upregulation of four genes (CTSB, SDC4, CTNND2, and FERMT2) in AD and uncovered three potential AD-associated genes (ITGB1BP1, FBXO33, and RASGEF1C). Our multi-modal MR study elucidated causal links between AD genetics and brain imaging-derived phenotypes (IDPs), with independent validation from both neuroimaging and transcriptomic analyses. These findings enhance understanding of AD etiology and identify potential MRI markers for diagnosis and treatment monitoring.},
}

@article {pmid41863703,
year = {2026},
author = {Al-Kuraishy, HM and Jabir, MS and Rafeeq, MF and Sulaiman, GM and Albuhadily, AK and Al-Gareeb, AI},
title = {Targeting of neuroinflammation, oxidative stress, and synaptic dysfunction by vinpocetine in alzheimer's disease: a comprehensive appraisal.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41863703},
issn = {1573-7365},
abstract = {Alzheimer disease (AD) is a neurodegenerative disease presented with progressive memory loss and cognitive impairment. Deposition of extracellular amyloid beta (Aβ) peptide and intracellular neurofibrillary tangles (NFTs) are the hallmarks of AD neuropathology. Progressive accumulation of Aβ and NFTs results in the development of inflammation/ neuroinflammation, oxidative stress, synaptic failure, neuronal apoptosis, and the development of AD. However, no single drug is effective as disease modifying treatment for AD, as many cellular and molecular signaling pathways beyond Aβ and NFTs are involved in AD neuropathology. Mounting evidences indicated that phosphodiesterase enzymes (PDEs) mainly PDE1 are involved in AD neuropathology. PDEs are intricate in the degradation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which are reduced in AD. Consequently, this review aims to revise the role of PDEs, and PDE1 selective inhibitor vinpocetine (VPN) in AD neuropathology. VPN by its anti-inflammatory and antioxidant effects can reduce inflammatory and oxidative stress in AD correspondingly. At molecular levels, VPN by targeting peroxisome proliferator activated receptor γ coactivator 1 α (PGC1α), brain derived neurotrophic factor (BDNF) and SIRT1 can mitigate AD neuropathology. Despite of these evidences, however there is limited clinical evidence for the efficacy of VPN in AD. Therefore, large-prospective clinical studies are warranted in this regard.},
}

@article {pmid41863721,
year = {2026},
author = {Maidh, A and Kalra, P and Khan, H and Silakari, P and Grewal, AK},
title = {Circadian disruption as a driver and target in neurodegenerative diseases: from molecular mechanisms to chronotherapeutic strategies.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41863721},
issn = {1573-7365},
abstract = {The Circadian System is a complex network of coordinated clocks that regulates the organism’s internal clock in synchronisation with the outside world. These rhythms are controlled by genetically controlled positive and negative transcriptional-translational feedback loops (TTFL) that generate 24-hour oscillations in the protein level and mRNA of core circadian components. Circadian disruption is recognised as a significant contributor to the molecular pathogenesis of neurodegenerative illnesses, as disease-specific alterations in clock gene expression and melatoninergic signalling have been identified as possible early-stage molecular indicators. Emerging evidence suggests a link between dysregulated circadian rhythms and neurodegenerative diseases, implying that the changes in circadian function may play a critical role in the development and progression of neurodegenerative diseases. The correlation between circadian rhythm and neurodegeneration is highly promising for developing treatment and promoting healthy lifestyle measures. This review article primarily focuses on how abnormalities in circadian rhythms may increase the risk of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Applying knowledge from pre-clinical and translational research on neurodegenerative diseases is crucial for lowering the risks of neurodegeneration and improving the symptoms and quality of life of people with neurodegenerative diseases through approaches that restore circadian rhythm in the context of precision medicine. Understanding this interaction holds promise for developing therapeutic approaches to support a healthy lifestyle.},
}

@article {pmid41910845,
year = {2026},
author = {Nekabari, MK and Ben-Azu, B and Chijioke, BS and Esuku, DT and Chidebe, EO and Friday, FB and Usin, SG and Iwhiwhu, P and Moses, AS and Diakparomre, O and Onyeukwu, OB},
title = {Lipopolysaccharide-induced Neuroimmune Alteration and Memory Decline in Aging Mice: The Role of Augmented Cellular Senescence.},
journal = {Neurotoxicity research},
volume = {44},
number = {2},
pages = {},
pmid = {41910845},
issn = {1476-3524},
abstract = {Alzheimer’s disease (AD) remains a complex neurodegenerative disorder with multifactorial etiologies, often eluding effective modeling in preclinical studies. However, whether neuroinflammation, exacerbated by accelerated cellular senescence, is central to AD pathology induced by lipopolysaccharide, an endotoxemia agent, remains unknown. This study investigated a combination of lipopolysaccharide (LPS)-induced AD-like neuroinflammation with doxycycline-induced conditioned cellular senescence in mice. Following a 21-day doxycycline (DOXY)-induced cellular senescence in mice, neuroinflammation was induced by LPS from days 15–21. AD-related cognitive decline was investigated through spatial and non-spatial memory tests, oxidative stress, molybdoenzymes, acetylcholinesterase activity, inflammation, amyloid-beta levels, hypoxia-inducible factor (HIF-α) and brain-derived neurotrophic factors (BDNF) in brain regions affected by AD pathology, such as the hippocampus and prefrontal cortex (PFC). Behavioral assessments revealed that both LPS and DOXY independently impaired spatial and non-spatial working memory, locomotor activity, social interaction, and recognition memory, with their interactive treatment exacerbating these deficits significantly. Biochemical analyses revealed synergistic increases in pro-inflammatory cytokines (IL-1β, TNF-α, but not IL-4), oxidative stress markers (malondialdehyde, nitrite), astrocyte activation (GFAP), and amyloid-beta levels, with decreases in antioxidant defenses (GSH, GST, SOD, catalase) in the hippocampus and PFC. The DOXY + LPS group showed higher serum corticosterone levels, increased sulphite-oxidase in the PFC, and increased xanthine-oxidase and acetylcholinesterase in both regions, indicating an amplified stress response and cholinergic dysfunction. Conversely, DOXY + LPS interaction lowered hippocampal-targeted BDNF and HIF-α levels. These findings validate the role of cellular senescence in enhancing LPS-induced neuroinflammation, mimicking complex AD features, and provide a model for testing disease mechanisms and therapeutics.},
}

@article {pmid41931192,
year = {2026},
author = {Du, M and Ma, S and Bai, L and Mou, X and Gao, Y and Zhang, J and Chen, Y},
title = {Olfactory Dysfunction Exacerbates Hippocampal Aβ Accumulation, Tau Phosphorylation and Memory Deficits in Mice.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41931192},
issn = {1573-6903},
support = {202401AU070130//Natural Science Foundation of Yunnan Province/ ; 202301AT070430//Natural Science Foundation of Yunnan Province/ ; 202305AS350011//innovation team of stress and disorder in nervous system in Yunnan Province/ ; 82201597//the National Natural Science Foundation of China/ ; KUST-KH2022001Y//the Joint Medical Specialization of Kunming University of Science and Technology/ ; },
abstract = {Olfactory dysfunction is a frequent feature in patients with neurodegenerative disorders such as Alzheimer’s disease (AD). However, whether olfactory impairment is the cause or consequence of AD is unknown. We previously found that olfactory dysfunction impairs learning and memory in mice in multiple experimental paradigms, but whether olfactory dysfunction increases AD-related neuropathological changes such as Aβ deposition and tau protein phosphorylation is not clear. In this study, mice were treated with bilateral intranasal zinc sulfate (ZnSO4) solution infusion, which resulted in olfactory dysfunction for about 1 month in mice. 1, 3, 6, and 9 months after that, the Y-maze learning and memory, as well as hippocampal Aβ deposition, tau and p-tau expression were tested. We found that olfactory dysfunction leads to a long period and irreversible learning and memory impairment in mice. Olfactory dysfunction also increased Aβ deposition, Aβ42 level, and increased p-tau expression in hippocampus (HPC), which were accompanied by increased beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and decreased presenilin-1 (PS1) expression. Compared with one time of ZnSO4 treatment, repetitive ZnSO4 treatment (three times, a month apart) resulted in more significant increases in tau phosphorylation in mice hippocampus. These results suggest that olfactory dysfunction lead to behavioral and pathological changes associated with AD in mice, which suggest that olfactory dysfunction can contribute to the development of AD.},
}

@article {pmid41944966,
year = {2026},
author = {Riaz, M and Qadir, H and Noman, M and Ahmed, S and Shah, FA and Malik, MU and Bashir, K and Farooq, U and Irshad, N},
title = {Mechanistic Insights into Bergapten by Modulation of Filamin A and GSK3β in STZ Induced Alzheimer's Disease: An Integrated In Silico, In Vitro and In Vivo Study.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41944966},
issn = {1573-6903},
abstract = {Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction and neuroinflammation. The study investigates bergapten (BGN) as a potential AD treatment. Computational analysis revealed strong binding affinity of BGN with Filamin A (FLNA) and glycogen synthase kinase-3β (GSK3β). In vitro assays demonstrated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition suggesting cholinergic modulation. In intracerebroventricular (i.c.v) streptozotocin (STZ) induced AD mice model, BGN (25 mg/kg, 50 mg/kg and 100 mg/kg i.p) was administered daily for 23 days. The blood and brain tissues samples were collected for biochemical and histopathological analysis. BGN showed dose-dependent cognitive improvements, with biochemical tests indicating renal and hepatic safety. Reduced C-reactive protein and lactate dehydrogenase levels suggested minimal systemic toxicity and neuroinflammation. Histology revealed preserved neurons, decreased amyloid deposits, and improved brain structure. Immunohistochemical analyses indicated BGN was associated with lower Tau, NF-κB, TLR4, and Caspase-3 expression and restored redox homeostasis. Critically, ELISA confirmed reduced FLNA along with Aβ and GSK-3β levels and thus highlights BGN novel modulation of this unexplored AD target. RT-PCR analysis showed downregulated expression of amyloid precursor protein, tau, discs large scaffold protein 4 and glial fibrillary acidic protein, while enhanced synaptic plasticity markers. Collectively, these findings suggest BGN as a promising multi-target neuroprotective and safer agent for AD.},
}

@article {pmid41945111,
year = {2026},
author = {Lai, Z and Zhang, B and Fu, Z and Li, R and Qian, Y and Zhang, Y and Xu, P and Du, Y},
title = {Research advances on Cordyceps sinensis and its components in relation to omics biomarkers for the neurological disorders.},
journal = {Die Naturwissenschaften},
volume = {113},
number = {3},
pages = {},
pmid = {41945111},
issn = {1432-1904},
support = {2026ZL0010//Zhejiang Traditional Chinese Medicine Science and Technology Program of China/ ; 82202605//National Natural Science Foundation of China/ ; 2023, DU YAOQIANG//Zhejiang Provincial Special Support Program for Cultivation of High-Level Innovative Health Talents of China/ ; },
abstract = {Cordyceps is a traditional medicinal fungus belonging to the species Ophiocordyceps sinensis. It grows in the alpine ecological zone of the Tibetan Plateau and exhibits dual characteristics of both insects and fungi. The primary species include Cordyceps sinensis and Cordyceps militaris. Rich in bioactive components such as cordycepin, polysaccharides, adenosine, and peptides, cordyceps demonstrates broad applications in immune regulation, anti-tumor activity, anti-inflammatory, and neuroprotection. Cordyceps sinensis and its components show great therapeutic potential in neurological diseases such as epilepsy, Alzheimer’s disease and Parkinson’s disease through multi-level and multi-target actions However, current research faces challenges including unclear mechanisms of action and insufficient clinical translation. In this review, we analyze the molecular mechanisms underlying cordyceps’ neuroprotective effects, including the regulating of apoptosis, improvement of mitochondrial function, and promoting of nerve repair. Utilizing network pharmacology, we explore the multi-targeted actions of cordyceps and predict the key pathways. Further we summarize the research progress in the integrated multi-omics analyses (genomics, transcriptomics, proteomics and metabolomics), to reveal the synergistic roles of cordyceps components in treating neurological disorders and identify potential molecular biomarkers. Additionally, we highlight the findings from preclinical experiments and animal models on cordyceps-based drugs, discussing their advantages and challenges for clinical application. Future studies should prioritize systematic exploration of standardized drug development, advanced multi-omics integration, and rigorous clinical trials. This will provide a more robust scientific foundation and practical guidance for the treatment of neurological diseases with cordyceps.},
}

@article {pmid42010038,
year = {2026},
author = {Nakatsuji, M and Shibano, M and Fujimori, K},
title = {Antioxidant Activity of Flavonoid Glabranin by Upregulating Antioxidant Gene Expression via MEK/ERK and PI3K/Akt Pathways in Human Neuroblastoma SH-SY5Y Cells.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42010038},
issn = {1573-6903},
support = {25ak0101219h0202//Japan Agency for Medical Research and Development/ ; },
abstract = {Oxidative stress is associated with neuronal cell death in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Glabranin, a flavonoid found in the stems and leaves of Glycyrrhiza glabra (licorice), exhibits antioxidant and anti-inflammatory properties. However, the effect of glabranin on the antioxidant response and the underlying mechanism including the specific signaling pathways, remain unclear. In the current study, we investigated the protective effect of glabranin on hydrogen peroxide (H2O2)-induced neurotoxicity in human neuroblastoma SH-SY5Y cells and its underlying mechanisms. H2O2-induced death of SH-SY5Y cells was restored by glabranin in a concentration-dependent manner. The number of H2O2-increased apoptotic cells was reduced by co-treatment with glabranin. Moreover, glabranin attenuated H2O2-induced cleaved caspase-3/7 levels. In addition, glabranin decreased H2O2-induced intracellular ROS levels via promoting the nuclear translocation of nuclear factor erythroid 2-related factor 2 and upregulating the antioxidant gene expression. Furthermore, glabranin enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) following H2O2 treatment. Inhibition of mitogen-activated protein kinase kinase (MEK)/ERK and phosphoinositide 3-kinase (PI3K)/Akt pathways abrogated glabranin-mediated elevation of antioxidant gene expression and neuroprotective effects. These findings suggest that glabranin mitigated H2O2-induced apoptosis by increasing the expression of antioxidant genes through activation of the MEK/ERK and PI3K/Akt pathways in SH-SY5Y cells. Therefore, glabranin has the potential to prevent and treat neurodegenerative diseases as an antioxidant agent.},
}

@article {pmid42050692,
year = {2026},
author = {Rahbek, MT and Kildegaard, H and Hallas, J and Ernst, MT and Lund, LC},
title = {Acetylcholinesterase inhibitors and the risk of delirium - a Danish nationwide register-based cohort study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02060-1},
pmid = {42050692},
issn = {1758-9193},
abstract = {BACKGROUND: Delirium is frequent in people with dementia and is linked to adverse outcomes. Disturbed cholinergic neurotransmission is implicated in its pathophysiology. We examined whether continuous use of acetylcholinesterase inhibitors (AChEIs) is associated with a reduced risk of incident delirium in patients with dementia. METHODS: Using Danish nationwide registries (2005–2024), we identified individuals ≥ 50 years initiating AChEIs. Continuous users (second prescription within 90 days) were compared with early discontinuers. Follow-up started 90 days after initiation and continued for up to 3 years. The outcome was a hospital discharge diagnosis of delirium (ICD-10 F05). Confounding was addressed using high-dimensional propensity score (hdPS) fine-stratification weighting, and Cox regression yielded hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Among 45,651 patients, 311 delirium events occurred among continuous users and 84 among early discontinuers, corresponding to incidence rates of 66 and 112 events per 10,000 person-years, respectively. The hdPS-weighted HR for delirium was 0.72 (95% CI 0.54–0.96). Results were consistent across sensitivity analyses and in patients with Alzheimer’s disease HR 0.68 (95% CI 0.48–0.96). A negative control outcome showed no association. CONCLUSIONS: Continuous AChEI treatment was associated with a lower risk of delirium. Findings support a potential benefit of maintaining therapy in routine dementia care, and possibly even in patients with minor intolerance to acetylcholinesterase inhibitors.},
}

@article {pmid42281500,
year = {2026},
author = {Rashidi, SK and Dezfouli, MA and Khalili, H and Kiani, AKD},
title = {The role of gut microbiota in the neurobiology and treatment of Alzheimer's disease.},
journal = {General physiology and biophysics},
volume = {45},
number = {2},
pages = {129-151},
doi = {10.4149/gpb_2025042},
pmid = {42281500},
issn = {0231-5882},
mesh = {Humans ; *Alzheimer Disease/therapy/microbiology/physiopathology ; *Gastrointestinal Microbiome ; Animals ; *Brain/physiopathology ; Amyloid beta-Peptides/metabolism ; Probiotics/therapeutic use ; Fecal Microbiota Transplantation ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia in the elderly population and characterized by progressive cognitive decline. The major pathological features of AD are the accumulation of extracellular amyloid-beta protein as neuritic plaques and intracellular hyperphosphorylated tau protein as neurofibrillary tangles. Studies have shown that gut microbiota are involved in several central nervous system disorders through regulation of neurotransmitter production, blood-brain barrier permeability and immune responses. The gut microbiota establishes a two-way communication between the gut and the brain through neural, endocrine, and immune pathways, which play a role in various neurological diseases, including AD. Alterations in the composition and function of the gut microbiota may influence neuroinflammation, amyloid-beta accumulation, and tau pathology. Targeting the balance of the gut microbiota through probiotics, prebiotics, and fecal microbial transplantation could be promising therapeutic approach against neurodegeneration. Understanding the complex relationship between the gut microbiota and AD pathobiology could pave the way for novel preventive and therapeutic strategies. Here, we summarized advances in the role of gut microbiota in AD pathobiology and updated rising concerns from recent reports. Moreover, the possibility of applying the capability of the gut microbiota as a promising treatment against AD has been discussed in this review.},
}

Humans
*Alzheimer Disease/therapy/microbiology/physiopathology
*Gastrointestinal Microbiome
Animals
*Brain/physiopathology
Amyloid beta-Peptides/metabolism
Probiotics/therapeutic use
Fecal Microbiota Transplantation

@article {pmid42281759,
year = {2025},
author = {Foye, G and Foye, E and Walter, S and Ptomey, LT},
title = {Research should be conducted with us, not on us: Perspectives on Alzheimer's disease clinical trials for persons with Down syndrome.},
journal = {Alzheimer's & dementia. Behavior & socioeconomics of aging},
volume = {1},
number = {4},
pages = {},
pmid = {42281759},
issn = {2997-3805},
abstract = {Life expectancy for individuals with Down syndrome (DS) has increased significantly over the past 60 years, drawing greater attention to Alzheimer's disease (AD), now the leading cause of death in this population. Despite a lifetime AD risk as high as 90%, individuals with DS have been historically excluded from AD research, exacerbating already-existing significant gaps in prevention, diagnosis, and treatment strategies. Although recent clinical trials have begun to address this, challenges in recruitment and retention persist due to accessibility barriers, safety concerns, and limited prior engagement. Meaningful inclusion requires centering the voices of both individuals with DS and their caregivers to ensure that researchers provide accessible studies, communicate with respect, and share results, which will result in greater trust in research. This perspective offers personal reflections from an adult with DS, her caregiver, and two researchers, offering practical insights for designing inclusive, respectful, and person-centered clinical trials.},
}

@article {pmid42282197,
year = {2026},
author = {Shao, Y and Yin, Y and Cheng, Y and McGeary, JE and Taveira, TH and Tsuang, DW and Logue, MW and Ayandeh, S and Ahmed, A and Zamrini, E and Zeng-Treitler, Q},
title = {Medication-Wide Association Study of Alzheimer's Disease and Related Dementias: Identifying Drug Candidates from Electronic Health Records through Explainable AI.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.02.26354752},
pmid = {42282197},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a leading cause of death and disability, and treatment options for Alzheimer's disease and related dementias (ADRD) remain limited. We applied a data-driven, mechanism-agnostic Medication-Wide Association Study Plus (MWAS+) framework to identify candidate medications associated with ADRD using longitudinal electronic health record data and explainable artificial intelligence (AI).

METHODS: We used Veterans Health Administration electronic health record data from January 1999 to May 2022. The initial study population comprised 8,424,715 Veterans aged 65 years or older. Cases were defined by ADRD-related diagnosis codes or ADRD-related medication prescriptions, and controls were free of ADRD diagnosis and ADRD-related medication use. After exclusions and matching on sex, race, age at first encounter, and duration of follow-up, the primary analytic cohort included 505,817 matched case-control pairs (1:1; 1,011,634 Veterans). Longitudinal features were extracted from historical data up to 1 year before the index date and aggregated into 1-year intervals. We developed an upgraded Hybrid Value-Aware Transformer (HVAT 2.0) to jointly learn from longitudinal and nonlongitudinal clinical data while incorporating numerical values associated with clinical concepts, including cumulative medication dose. To enhance interpretability, we applied a medication-specific impact score method to estimate model-derived associations between medication exposure and ADRD risk.

FINDINGS: The model demonstrated stable performance across data partitions, with area under the receiver operating characteristic curve values of 0.791 in the training set, 0.772 in the validation set, and 0.775 in the testing set. Metolazone and varenicline were identified as the top 2 candidate medications with negative impact scores, suggesting potentially protective associations with new-onset ADRD. The impact score was -0.196 per unit of cumulative dose for metolazone (1800 mg) and -0.134 per unit for varenicline (280 mg). Although individual-level impact scores varied, most exposed patients had negative scores, including 12,020 of 12,480 metolazone users (96%) and 8,341 of 8,786 varenicline users (95%).

IMPLICATIONS: This study demonstrates the feasibility of combining a medication-wide association framework, longitudinal dose-aware modeling, and explainable AI to identify candidate medications for ADRD from real-world electronic health record data. The findings should be interpreted as signals for hypothesis generation rather than evidence of causality. This framework may support prioritization of repurposing candidates for expert review, follow-up cohort validation, and future clinical investigation.},
}

@article {pmid42282265,
year = {2026},
author = {Kwa, E and Ogilvie, CE and Kormos, NC and Green, AJE and Smith, TK and Gunn-Moore, FJ},
title = {The inhibitors of 17β-HSD10: are they any good?.},
journal = {RSC chemical biology},
volume = {},
number = {},
pages = {},
pmid = {42282265},
issn = {2633-0679},
abstract = {The advent of the first disease-modifying therapies for Alzheimer's disease (AD) has renewed optimism for effective prevention and treatment strategies. Growing mechanistic insights indicate that AD pathogenesis is multifactorial and non-linear, better conceptualized as a circular vortex in which interconnected pathological processes reinforce one another. This complexity highlights the necessity for multiple druggable targets and combination-based therapeutic approaches. A hallmark of AD is reduced cerebral glucose utilization, revealed by positron emission tomography studies, reflecting profound metabolic disruption and mitochondrial dysfunction. Among mitochondrial candidates, 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), encoded by HSD17B10, has emerged as a protein of interest. Despite debate surrounding its substrate specificity due to conflicting in vitro data, its elevated expression in neurons and astrocytes within AD brains underscores its potential relevance. This review outlines chemical entities targeting both catalytic and non-catalytic functions of 17β-HSD10 and examines whether its inhibition offers biological efficacy and clarifies its metabolic roles in the living brain.},
}

@article {pmid42282664,
year = {2026},
author = {Fang, X and Border, JJ and Zhang, H and Morgan, GC and Gregory, A and Hanscom-Trofy, Y and Dong, R and Yang, J and Hwang, SH and Morisseau, C and Hammock, BD and Fan, F and Roman, RJ},
title = {Inhibition of Soluble Epoxide Hydrolase Rescues Cognitive Deficits by Preserving Neurovascular Integrity and Attenuating Glial- and Neuropathology in Diabetic-Related Dementia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.01.729327},
pmid = {42282664},
issn = {2692-8205},
abstract = {Diabetes mellitus (DM) is a major risk factor contributing to the development of Alzheimer's disease-related dementias (ADRD). While one of the early symptoms of both Alzheimer's disease (AD) and DM-related ADRD is a reduction in cerebral blood flow, the underlying biological mechanisms driving this decline remain to be fully elucidated. Genome-wide association studies have linked AD/ADRD to single-nucleotide polymorphisms in the gene encoding soluble epoxide hydrolase (sEH), an enzyme we previously reported to be upregulated in the brains of an AD rat model. Our previous work also demonstrated that chronic inhibition of sEH with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) preserves hippocampal-dependent spatial learning and memory and improves cerebral hemodynamics in both AD and DM-ADRD models. In the present study, we found that chronic TPPU treatment (1 mg/kg/day for 9 weeks) reduced brain sEH expression, improved cortical-based long-term non-spatial recognition memory involving both cortical and hippocampal networks, and reduced anxiety in DM-ADRD rats. TPPU improved brain perfusion and normalized impaired whisker-evoked functional hyperemia, an effect linked to upregulation of Kir2.1 expression in cerebral capillaries. Furthermore, TPPU restored tight junction proteins (ZO-1 and OCLN), mitigated capillary rarefaction, and suppressed astrocyte and microglial activation. At the cellular level, TPPU attenuated hippocampal neurodegeneration, restored the expression of synaptic proteins (PSD95 and SY38), and reduced levels of key pro-inflammatory chemokines, including MCP-1, RANTES, and MIP-1α, in DM-ADRD. In conclusion, TPPU preserves cognitive function in DM-ADRD by mitigating cerebrovascular dysfunction, neuroinflammation, and gliosis while protecting synaptic integrity and neuronal survival, representing a promising therapeutic strategy for DM-ADRD.},
}

@article {pmid42283246,
year = {2026},
author = {Fikry, H and Saleh, LA and Sadek, DR},
title = {Histological and Tissue-Level Outcomes of Stem Cell Therapies in Neurodegenerative Disorders: A Systematic Review.},
journal = {Clinical anatomy (New York, N.Y.)},
volume = {},
number = {},
pages = {},
doi = {10.1002/ca.70147},
pmid = {42283246},
issn = {1098-2353},
abstract = {Neurodegenerative diseases, which afflict millions worldwide and threaten public health, have no cure. Neurodegenerative diseases lack effective therapies, burdening society and the economy. Over the past 20 years, regenerative cell therapy (stem cell therapy) has advanced, opening novel neurodegenerative disease treatments. Thus, the current review aimed to systematically highlight experimental and clinical studies of potentially effective therapeutic strategies for stem cells and report histological, cellular, or ultrastructural outcomes following stem cell interventions in neurodegenerative diseases. PRISMA-compliant computerized literature searches of PubMed, Scopus, and Web of Science identified studies on embryonic, induced pluripotent, mesenchymal, or neural stem cells (NSCs) in neurodegenerative disease models and histological and tissue-level outcomes. Search terms included nervous system diseases, histology, neuron regeneration, stem cells, stem cell treatment, and transplantation. Peer-reviewed articles published between 2000 and 2025 were selected. Experimental animal and clinical studies that reported histological or tissue-level results after stem cell treatments were included. Eighty-six studies met the eligibility criteria, covering models of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease. Across these studies, stem cell therapies were linked to improved neuron survival, better synaptic structure, diminished gliosis, and some restoration of tissue structure. These effects depended on the type of stem cell used, the disease model, and how the treatment was given. Overall, the evidence suggests that stem cell therapies can lead to significant histological and tissue-level improvements in neurodegenerative diseases, supporting their potential for regeneration. Further standardized and translational studies are needed to clarify the underlying mechanisms and improve treatment strategies.},
}

@article {pmid42283996,
year = {2026},
author = {Totuk, O},
title = {Amyloid-Related Imaging Abnormalities in Anti-amyloid Therapy: Clinical Implications of Kinetics for Safer Use and Risk Stratification.},
journal = {Clinical drug investigation},
volume = {},
number = {},
pages = {},
pmid = {42283996},
issn = {1179-1918},
abstract = {Anti-amyloid monoclonal antibodies have emerged as disease-modifying therapies for Alzheimer's disease. However, their broader clinical adoption is limited by amyloid-related imaging abnormalities, a key safety concern. Traditionally viewed as an unavoidable and dose-dependent adverse effect, amyloid-related imaging abnormalities often lead to treatment interruption or the exclusion of high-risk patients from therapy. Emerging evidence now suggests that amyloid-related imaging abnormalities may instead reflect a transient modifiable cerebrovascular response, primarily influenced by the kinetics of amyloid clearance rather than the absolute magnitude of amyloid removal. Recent data from titration-based dosing strategies demonstrate that gradual amyloid mobilization can significantly reduce the incidence of amyloid-related imaging abnormalities without compromising amyloid positron emission tomography responses or downstream biomarkers. This kinetic perspective may support a more nuanced re-evaluation of patient groups previously deemed unsuitable for therapy, including APOE ε4 carriers, individuals with cerebral microbleeds, and patients on antithrombotic treatment. In this Current Opinion, we propose a pragmatic clinical framework that integrates amyloid clearance kinetics, magnetic resonance imaging-based risk stratification, and individualized protocols for treatment interruption and re-challenge. By reframing amyloid-related imaging abnormalities as a modifiable clinical decision-making challenge rather than an inherent toxicity, anti-amyloid therapies may be optimized for safer use; however, whether such approaches can enable broader and more inclusive treatment strategies remains to be established in prospective studies, particularly in high-risk populations.},
}

@article {pmid42284682,
year = {2026},
author = {O'Brien, EK and Cox, T and Fernandez, S and Bourgeat, P and Porter, T and Goudey, B and Doecke, JD and Masters, CL and Fripp, J and Nho, K and Villemagne, VL and Cruchaga, C and Rowe, CC and Saykin, AJ and Doré, V and Laws, SM},
title = {Predicting accumulation and age at onset of amyloid-β from genetic risk and resilience for Alzheimer's disease.},
journal = {EBioMedicine},
volume = {129},
number = {},
pages = {106329},
doi = {10.1016/j.ebiom.2026.106329},
pmid = {42284682},
issn = {2352-3964},
abstract = {BACKGROUND: Accumulation of brain amyloid beta (Aβ), a key pathological hallmark of Alzheimer's disease (AD), begins decades before cognitive symptoms. Being able to predict the risk of Aβ accumulation, or the age at which Aβ exceeds a critical threshold, may enable intervention to delay or prevent onset of AD.

METHODS: Using published genome-wide association studies (GWASs), we developed polygenic scores (PGS) for AD risk (PGSrisk) and resilience (PGSresilience), and tested whether these predicted (i) if an individual is an Aβ accumulator ('Accumulator Status'), and (ii) in accumulators, the age at which brain Aβ exceeds a 20 centiloid (CL) threshold ('Age at onset of Aβ'; AAO-Aβ) in 2175 participants (1158 with AAO-Aβ) from the Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study. We also performed GWASs on these traits to develop phenotype-specific PGSs.

FINDINGS: Higher genetic risk of AD predicted increased odds of Aβ accumulation (OR = 1.16; 95% CI = 1.05-1.29; p = 0.003) and younger AAO-Aβ (β = -1.32; SE = 0.31; p = 1.63 × 10[-5]). Higher genetic resilience to AD predicted later AAO-Aβ (β = 0.91; SE = 0.29; p = 0.002) but did not predict Aβ accumulation. These associations were independent of APOE ε4 status, the strongest genetic risk factor for AD. Phenotype-specific PGSs were not significantly associated with either trait.

INTERPRETATION: Polygenic scores, alongside other risk factors, may help identify individuals at risk of accumulating Aβ, and predict the age at which this exceeds a critical threshold. This could provide a window for administering disease-modifying treatment or lifestyle interventions to prevent or delay the onset of AD.

FUNDING: National Institutes of Health (R01-AG058676-01A1) and Australian National Health and Medical Research Council (GNT1161706; GNT2001320).},
}

@article {pmid42288063,
year = {2026},
author = {Zhao, H and Qian, S and Wang, Y and Yang, W},
title = {Information quality of Alzheimer's disease treatment videos on TikTok and related factors: A cross-sectional study.},
journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia},
volume = {152},
number = {},
pages = {112144},
doi = {10.1016/j.jocn.2026.112144},
pmid = {42288063},
issn = {1532-2653},
abstract = {BACKGROUND: The increasing reliance on mobile internet for health information necessitates a critical evaluation of content quality. This study aimed to systematically assess the quality of Alzheimer's Disease (AD) treatment-related short videos on TikTok, a leading platform for health information dissemination.

METHOD: A total of 100 CE treatment videos from TikTok, retrieved on December 20, 2025, were comprehensively evaluated using established assessment tools. Specifically, the Journal of American Medical Association (JAMA) benchmark criteriaand themodified Decision-making Information Support Criteria for Evaluating the Reliability of Non-randomised Studies (mDIS) scorewere used to evaluate thereliabilityof the video content. TheGlobal Quality Score (GQS) was used to assess theoverall quality, and the Patient Education Materials Assessment Tool for Audio Visual Content (PEMAT-A/U)was used to evaluate understandability and actionability.

RESULTS: Neurologists were identified as primary contributors of high-quality content, while videos on experimental treatments like deep cervical lymphovenous anastomosis (LVA) generally exhibited lower quality. Videos from emerging first-tier cities and those uploaded by top-tier creators demonstrated superior audience engagement and often higher content quality. A significant positive correlation was found between video duration, audience engagement metrics, and content quality scores.

CONCLUSIONS: Neurologists play a crucial role in providing reliable AD treatment information on short video platforms. There is an urgent need to improve the quality of content on experimental treatments and to encourage longer, well-referenced videos. Platforms should enhance content moderation and explicitly label experimental therapies to ensure accurate and trustworthy public health education regarding AD.},
}

@article {pmid42289507,
year = {2026},
author = {Yazi, S and Ozen, B and Buldu, B and Yalcin, E and Karakose, O and Cakmak, O and Somunkiran, S and Yananli, HR and Sehirli, US and Kirazli, O},
title = {The effect of canagliflozin on hippocampal dendrite morphology in a model of Alzheimer's disease induced by intracerebroventricular injection of streptozotocin.},
journal = {Brain structure & function},
volume = {231},
number = {6},
pages = {},
pmid = {42289507},
issn = {1863-2661},
mesh = {Animals ; *Canagliflozin/pharmacology/administration & dosage ; *Alzheimer Disease/pathology/chemically induced/drug therapy ; Male ; Streptozocin/administration & dosage ; *Dendrites/drug effects/pathology ; Rats ; *Hippocampus/drug effects/pathology ; Disease Models, Animal ; Donepezil/pharmacology ; Dendritic Spines/drug effects/pathology ; Pyramidal Cells/drug effects/pathology ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; Rats, Wistar ; Rats, Sprague-Dawley ; },
abstract = {Alzheimer's disease (AD) and diabetes mellitus (DM) share common pathophysiological features. However, the effects of antidiabetic drugs on neurodegeneration are not completely known. Canagliflozin, a novel option for DM treatment, is a dual inhibitor of sodium glucose co-transporter type 2 (SGLT2) and acetylcholinesterase. The aim of this study is to examine the morphological features of dendrites and dendritic spines of pyramidal neurons in hippocampus of AD model treated with canagliflozin. The model of AD was obtained by intracerebroventricular injection of streptozotocin. Then, the rats were divided into 3 groups: vehicle, donepezil, and canagliflozin. The injections were i.c.v. administered for 7 days. Behavioral tests were performed to evaluate memory, anxiety, and motor functions. Brain tissues were processed by Golgi impregnation method. Pyramidal neurons in the CA1 region were examined using Neurolucida software. Dendritic branching, total dendrite length, dendritic spine density, and dendritic spine types were analyzed. Compared to the vehicle group, the donepezil group and the canagliflozin group exhibited significantly higher dendritic branches (p = 0.0273, p = 0.0195) and total dendrite length (p = 0.0171, p = 0.0360), respectively. The total dendritic spine density (p < 0.0001) and the mushroom-type dendritic spine density (p = 0.0001) were significantly low in the donepezil group compared to the vehicle group. However, canagliflozin did not induce any significant alterations in the dendritic spine density. Canagliflozin treatment was as effective as donepezil treatment on hippocampal dendrite morphology. This morphological framework, indicating dendritic plasticity and remodeling, serve to better understand the cellular effects of canagliflozin. Therefore, our study may contribute to the development of novel strategies for therapy of AD.},
}

Animals
*Canagliflozin/pharmacology/administration & dosage
*Alzheimer Disease/pathology/chemically induced/drug therapy
Male
Streptozocin/administration & dosage
*Dendrites/drug effects/pathology
Rats
*Hippocampus/drug effects/pathology
Disease Models, Animal
Donepezil/pharmacology
Dendritic Spines/drug effects/pathology
Pyramidal Cells/drug effects/pathology
*Sodium-Glucose Transporter 2 Inhibitors/pharmacology
Rats, Wistar
Rats, Sprague-Dawley

@article {pmid42291413,
year = {2026},
author = {Sha, Y and Fu, H and Lu, K and Wang, G and Wang, Y},
title = {The role of YKL-40 in Alzheimer's disease pathology and drug targeting.},
journal = {PeerJ},
volume = {14},
number = {},
pages = {e21361},
pmid = {42291413},
issn = {2167-8359},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Chitinase-3-Like Protein 1/metabolism/antagonists & inhibitors ; Animals ; Biomarkers/metabolism ; Apoptosis ; Disease Progression ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques, hyperphosphorylated tau tangles, and significant neuronal loss. Recent studies have implicated YKL-40, a glycoprotein commonly associated with inflammation and neural apoptosis, in the pathogenesis of AD.

METHODS: We conducted extensive searches across major scientific databases, including PubMed, Web of Science, and Embase. We selected peer-reviewed articles, review articles, and clinical studies focusing on YKL-40 in AD.

RESULTS: This review comprehensively analyses the multifaceted role of YKL-40 in AD, covering its cellular localization, biomarker associations, and pathological mechanisms. We also summarize the mechanistic pathways by which YKL-40 contributes to disease progression, highlighting its role in neuroinflammation, neural apoptosis, and disruption of the circadian regulation of immune responses. Moreover, the development of drugs that target YKL-40, such as humanized anti-YKL-40 antibodies and small molecules, offers promising strategies for blocking AD progression.

CONCLUSION: This review highlights the potential of YKL-40 as a novel drug target and its implications for enhancing diagnostic precision and treatment strategies in combating Alzheimer's disease.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Chitinase-3-Like Protein 1/metabolism/antagonists & inhibitors
Animals
Biomarkers/metabolism
Apoptosis
Disease Progression

@article {pmid42292330,
year = {2026},
author = {Mukhopadhyay, D and Das, P and Angom, RS and Dutta, S and Li, Z and Castanedes-Casey, M and Kulkarni, T and Chakravarty, T and Wang, E and Dickson, D and Rachamala, HK},
title = {Vascular endothelial growth factor receptor-1 (VEGFR-1) knock-down is protective against hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril -induced neuronal cell death: implications in AD pathogenesis.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1799391},
pmid = {42292330},
issn = {1662-4548},
abstract = {INTRODUCTION: Recent transcriptome analysis has demonstrated increased expression of Vascular Endothelial Growth Factor receptor-1 (VEGFR-1/FLT1) and in AD brain. Increased expression of VEGFR1 and its ligand VEGFB were associated with a more rapid rate of cognitive decline, providing evidence of a potential link between increased VEGFR-1 expression in AD pathogenesis. In this study, we explored the potential role of VEGFR-1 expression in neurons on AD pathology.

METHODS: To confirm VEGFR1 expression in AD brains, we first performed immunostaining in AD brain sections (AD - Braak stage V-VI, and normal controls - Braak 0-II). And to determine a potential detrimental role of neuronal VEGFR1 expression on AD associated pathologies, we exposed SH-SY5Y human neuroblastoma cells and mouse primary neurons to either hypoxia conditions (1%O2) or 5 μ Aβ1-42 oligomers or fibrils for 24, 28 and 72hrs.

RESULTS: In this study, we found preferential staining of VEGFR-1 in the neuropil and neuronal cell bodies both in AD and Control hippocampus and increased VEGFR-1 immunoreactivity in dystrophic neuritic processes in the vicinity of Thio-S positive amyloid plaques in AD brains. And treatment of SH-SY5Y human neuroblastoma cell line and mouse primary neurons, with either hypoxia conditions or Aβ1-42 oligomers, resulted in increased VEGFR-1 expression and cleaved caspase 3 activation, leading to neuronal toxicities/cell death. Similarly, treatment with Aβ1-42 fibrils also increased VEGFR-1 and cleaved caspase 3 protein levels in the SH-SY5Y cells whereas treatment with Aβ1-42 monomers had no effect on VEGFR-1 expression. In addition, we show that over-expression of VEGFR-1 intracellular domains in SH-SY5Y cells directly induced neuronal toxicities and importantly, siRNA-mediated knockdown of VEGFR-1 in neurons prevented the hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril-induced toxicities and cell death phenotypes. Treatment with either hypoxia or Aβ1-42 oligomers also reduced expression of cell survival genes including VEGFR-2 and Hippo pathway YAP1 and siRNA-mediated VEGFR-1 knockdown in the neurons normalized expression of both VEGFR-2 and YAP1. Using differential gene expression analysis, we demonstrated upregulation of several inflammatory/interferon-stimulated genes (ISGs) as well as increased expression of genes involved in activation of oxidative stress and cell death pathways in response to Aβ1-42 oligomers treatment in mouse primary neurons. And siRNA-mediated VEGFR-1 knockdown in the mouse primary neurons, reduced gene expression of both the ISGs and oxidative stress/cell death pathways in response to Aβ1-42 oligomer treatment.

DISCUSSION: In summary, these results show that siRNA-mediated knockdown of VEGFR-1 in neurons significantly prevented hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril-induced cellular toxicities and cell death phenotypes, indicating a potential detrimental role of aberrant VEGFR-1 expression and signaling in response to AD associated pathologies.},
}

@article {pmid42292846,
year = {2026},
author = {Lindemann, L and Lambotte, J and Rothe, J and Messer, J and Diener, C and Pichereau, S and Cantrill, C and Mueggler, T and Honer, M and Beck, J and Steinbrecher, T and Tortelli, R and Gerlach, I and Ratni, H and Rodriguez Sarmiento, RM and Baumann, K},
title = {Pharmacology of nivegacetor (RG6289), a potent and selective gamma secretase modulator in clinical development for the treatment of Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1783414},
pmid = {42292846},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a prevalent neurodegenerative disorder which involves a complex pathobiology driven by amyloid-beta (Aβ) and tau pathologies, among other factors. Aβ peptides are generated via β-secretase (BACE1) and γ-secretase cleavage of amyloid precursor protein (APP). While long isoforms like Aβ42 are neurotoxic and aggregation-prone, shorter isoforms (Aβ38, Aβ37) are non-amyloidogenic. γ-secretase modulators (GSMs) shift production from longer to shorter peptides which is expected to slow down or halt (prevent) amyloid accumulation and its downstream effects.

METHODS: The novel GSM nivegacetor was evaluated in vitro using cell lines overexpressing human wild-type APP, or human APP with the Swedish mutation K670N/M671L (APPSwe). The in vitro selectivity of nivegacetor was tested on Notch-1, a representative gamma secretase substrate other than APP. Additionally, nivegacetor was profiled for its selectivity on a range of pharmacological targets. In vivo studies tested a dose-response and a time course of nivegacetor on soluble Aβ levels in brain tissue of APPSwe transgenic mice. Furthermore, the impact of two ADAD mutations, PSEN1 E280A (Columbian) and PSEN2 N141I (Volga German), on nivegacetor's potency was tested. Moreover, nivegacetor was tested for possible effects on [[3]H]florbetaben binding to Aβ plaque pathology in human AD brain tissue sections.

RESULTS: Nivegacetor lowered the production of Aβ42 and Aβ40 and concomitantly increased levels of Aβ37 and Aβ38 in vitro and in vivo in mice. Nivegacetor did not inhibit Notch-1 and showed a favorable selectivity profile on a broad range of targets. When tested on two ADAD mutations, nivegacetor was equipotent on the PSEN1 E280A mutation and significantly less potent on the PSEN2 N141I mutation compared to wild-type gamma secretase. Nivegacetor did not interfere with the detection of amyloid plaques by [[3]H]florbetaben in human AD brain tissue, which is an important prerequisite for the use of florbetaben as a PET tracer in clinical trials.

CONCLUSION: Nivegacetor is a potent, orally bioavailable GSM with favorable properties and is currently under investigation as a clinical candidate in a Phase 2A clinical trial in individuals with prodromal and early sporadic AD, and in a Phase 2 clinical trial in individuals carrying the PSEN1 E280A ADAD mutation.},
}

@article {pmid42274866,
year = {2026},
author = {Lefcourt, S and Kim, A and Huang, P and Weiss, C and , and Jones, C},
title = {Multi-scale Radiomic Fingerprint: Quantifying Spatial Changes in Biology.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10278-026-02041-8},
pmid = {42274866},
issn = {2948-2933},
support = {HT9425-23-1-0032//U.S. Department of Defense/ ; },
abstract = {Traditional radiomic studies build texture matrices using single-voxel increments. However, useful information may emerge when radiomic features are instead evaluated across multiple spatial scales. Moreover, basing these scales on physical units may produce results that are more interpretable to clinicians. We propose a multi-scale radiomic approach that defines texture distances in millimeter-based units to capture a more inclusive range of texture information, promote reproducibility, and improve clinician interpretability. We examine the variance in quantified radiomics across multiple spatial scales and diseases, including venous malformations, gliomas, Alzheimer's disease, brain metastases, and multiple sclerosis. We subsequently generated anisotropic counterparts to originally isotropic datasets to compare their performance in clinical predictive modeling. Finally, we evaluate differences between radiomic features captured at millimeter and voxel units. We discovered that the radiomic features captured at different millimeter scales were almost always statistically different (p < 0.05) across five diseases. Predictive modeling revealed that models trained on radiomics extracted from multiple millimeter scales consistently had a higher mean F1 across folds compared to those built from voxel scales. Roughly 93%, 90%, and 88% of texture metrics were statistically different between millimeter and voxel scales for venous malformations, Alzheimer's, and gliomas, respectively, suggesting that variations in spatial scale may capture differences in biology. We demonstrate that a multi-scale, millimeter-based alternative to fixed-distance voxel-based radiomics captures previously unacquired textural information while remaining clinically interpretable. This approach may have broad implications in all applications of clinical radiomic analysis, including disease diagnosis, monitoring, and treatment evaluation.},
}

@article {pmid42274906,
year = {2026},
author = {He, Y and Yi, T and Min, M and Xu, K and Lin, H and Xu, R and Deng, D and Xiao, X},
title = {Environmental Factors Drive Neurodegenerative Diseases Through Glutamate Excitotoxicity: A Convergent Mechanistic Pathway.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {42274906},
issn = {1995-8218},
abstract = {This review illustrates how environmental stressors disrupt glutamate homeostasis via specific mechanisms: lead-induced thiol modification, manganese mediated yin yang 1 (YY1)-histone deacetylases (HDAC) repression, PM2.5-triggered microglia-astrocyte crosstalk, and advanced glycation end products (AGEs)-receptor for advanced glycation end products (RAGE)-nuclear factor kappa-B (NF-κB) signaling from high-sugar diets. Together with genetic susceptibility and pigment epithelium-derived factor (PEDF), these factors impair astrocytic glutamate uptake, promoting synaptic glutamate accumulation. Subsequent N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor overactivation triggers calcium overload, mitochondrial dysfunction, oxidative stress, and neuroinflammation-termed "degenerative excitotoxicity". Excitotoxicity manifests in Alzheimer's disease (amyloid-beta-excitatory amino acid transporter 2 (EAAT2) interplay), Parkinson's disease (subthalamic nucleus-driven excitatory storm), and amyotrophic lateral sclerosis (astrocytic failure versus neuronal cell-autonomous mechanisms). Future interventions need multi-target strategies, emerging technologies, and lifestyle modifications. This convergent framework offers a unified understanding linking environmental exposure to neurodegeneration and charts a roadmap toward mechanism-based prevention and treatment.},
}

@article {pmid42275797,
year = {2026},
author = {Lahiri, D and Kathir, S and Punjwani, Z and Liu, A and Pasvanis, S and Seixas-Lima, B and Roncero, CT and Chertkow, H and , },
title = {Application of a clinical scale for predicting Aβ-positivity in a multicentre Canadian dementia cohort: A necessity in the era of amyloid targeting treatment.},
journal = {Journal of the neurological sciences},
volume = {488},
number = {},
pages = {126047},
doi = {10.1016/j.jns.2026.126047},
pmid = {42275797},
issn = {1878-5883},
abstract = {BACKGROUND: Clinical Amyloid positivity Prediction Score (CAPS) is a clinical tool developed on a small Canadian cohort with clinical Alzheimer's Disease (AD) to help predict amyloid-beta (Aβ) positivity. The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study is a national Canadian observational study of participants clinically diagnosed with various neurodegenerative disorders, including Alzheimer's syndrome, making it an ideal platform to validate CAPS on an independent but similar cohort of participants.

METHODS: Participants from the COMPASS-ND cohort with Subjective Cognitive Impairment (SCI), Mild Cognitive Impairment (MCI) or dementia due to AD, and a known Aβ status were included. CAPS was assigned to the individuals as follows: cognitive decline of >2 points/year on the Mini-Mental State Examination (MMSE) = 1-point, Neuropsychiatric Inventory Questionnaire (NPI-Q) ≥2 = 2 points, and low Fazekas score (0 or 1) = 1 points. A total CAP score ≥ 2 was considered indicative of Aβ positivity.

RESULTS: Total 86 participants fulfilled the inclusion criteria. Aβ + individuals had higher NPI-Q scores (2 vs 0.5, p = 0.005) and a lower baseline MMSE score (26.5 vs 28.0, p = 0.009). High WMH on brain MRI was reported more frequently in the Aβ- subgroup (50.0% vs 33.8%, p < 0.001). The frequency of people with a CAPS score of ≥2 is significantly higher in the Aβ + subgroup (75% vs 50%, p < 0.001). CAPS demonstrated a reasonable predictive value in this cohort, with 67% accuracy, and 73% sensitivity.

CONCLUSION: This validation study in a larger Canadian cohort showed that CAPS demonstrated reasonable accuracy in distinguishing between Aβ + and Aβ- subgroups.},
}

@article {pmid42276063,
year = {2026},
author = {Ishikawa, KI and Shiga, T and Hirose, T and Kuzumaki, N and Miyoshi, S and Yamaguchi, A and Tamune, H and Sarkar, AK and Nakai, K and Baba, K and Okabe, S and Hattori, N and Okano, H and Akamatsu, W},
title = {Suppression of ATM kinase signaling accelerates cellular senescence.},
journal = {Stem cell reports},
volume = {},
number = {},
pages = {102956},
doi = {10.1016/j.stemcr.2026.102956},
pmid = {42276063},
issn = {2213-6711},
abstract = {Cells derived from rejuvenated human induced pluripotent stem cells (hiPSCs) require extended culture periods to achieve functional maturation, and it remains difficult to recapitulate cellular senescence in these cells in vitro. This limitation hinders the accurate and efficient modeling of age-related neurodegenerative diseases. Here, we aimed to establish a simple approach to promote neuronal maturation and improve the efficiency of hiPSC-based disease modeling. Using a small-molecule inhibitor library, we identified an ATM kinase inhibitor, KU60019, that promotes both maturation-associated features and senescence-associated phenotypes in hiPSC-derived neurons and fibroblasts. KU60019 treatment promoted the manifestation of disease-relevant phenotypes in hiPSC models of age-related neurodegenerative diseases. Furthermore, senolytic analyses suggested that KU60019-induced senescent cells depend on pro-survival pathways, including HSP90-associated signaling. These findings suggest that KU60019 provides a simple and useful tool for accelerating phenotypic recapitulation in hiPSC models of age-related neurodegenerative diseases.},
}

@article {pmid42276200,
year = {2026},
author = {Alruwaili, NS and Al-Kuraishy, HM and Al-Gareeb, AI and Shokr, MM and Bogari, NM and Alhelfawi, S and Alruwaili, M and Batiha, GE},
title = {Beyond categorical boundaries: Common molecular and cellular pathways in autism spectrum disorder and schizophrenia.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111774},
doi = {10.1016/j.pnpbp.2026.111774},
pmid = {42276200},
issn = {1878-4216},
abstract = {Historically, ASD and schizophrenia have been classified as two distinct disorders, one being a neurodevelopmental disorder and the other a psychotic disorder. Recent studies, however, suggest that there may be substantial overlap between these disorders. Here, we will discuss some of the biological mechanisms involved in the development of these diseases that show similarities. These include dysregulation of the dopaminergic, serotonergic, glutamatergic, GABAergic, and acetylcholinergic systems; changes in BDNF signaling; histamine dysregulation; microglial activation; neuroinflammation; complement-mediated synapse elimination; gut-brain axis signaling; and endocannabinoid system dysfunction. It is important to note that the aforementioned biological mechanisms are present in several CNS disorders, such as major depressive disorder, Alzheimer's disease, and multiple sclerosis. While it is true that other CNS disorders share the same biological mechanisms as ASD and schizophrenia, the similarity between these disorders stands out for a particular reason. First, the biological mechanisms present in ASD and schizophrenia are significantly similar; second, their heritability is highly consistent; third, they have similar developmental trajectories; fourth, they exhibit similar circuit-level pathology; fifth, they share bidirectional epidemiological risks; and sixth, they follow a neurodevelopmental continuum. Recognizing this overlap has potential implications for early detection, biomarker development, and transdiagnostic treatment strategies, including repurposing medications such as memantine, α7-nicotinic agonists, and anti-inflammatory agents. However, longitudinal studies are needed to determine whether early targeting of shared pathways modifies long-term psychosis risk in ASD.},
}

@article {pmid42276536,
year = {2026},
author = {Kshirsagar, S and Reddy, AP and Reddy, PH},
title = {Restoration of mitochondrial dynamics and synaptic function by mitophagy enhancers in a tauopathy cell model.},
journal = {Mitochondrion},
volume = {},
number = {},
pages = {102184},
doi = {10.1016/j.mito.2026.102184},
pmid = {42276536},
issn = {1872-8278},
abstract = {OBJECTIVES: To evaluate whether mitophagy enhancers-including urolithin A, actinonin, tomatidine, and nicotinamide riboside-can counteract mitochondrial dysfunction and synaptic damage induced by phosphorylated Tau in Alzheimer's disease.

METHODS: We Used immortalized mouse hippocampal primary HT22 neurons expressing mutant Tau (mTau-HT22). We treated cells with mitophagy enhancers and measured gene and protein levels of mitochondrial dynamics, biogenesis, mitophagy, synaptic markers, assessed cell viability, mitochondrial respiration, and examined mitochondrial morphology via transmission electron microscopy.

RESULTS: Compared to controls, mTau-HT22 cells exhibited increased mitochondrial fission and reduced fusion, diminished mitochondrial biogenesis, impaired mitophagy and synaptic gene expression, reduced cell survival, lower respiration, and fragmented mitochondria. Treatment with all mitophagy-enhancing compounds improved mitochondrial dynamics-, biogenesis-, and mitophagy-related marker expression together with mitochondrial functional outcomes, with urolithin A showing the strongest effects. Notably, a combined treatment of urolithin A with EGCG further enhanced respiratory function beyond single-agent treatments.

CONCLUSIONS: Mitophagy enhancers, particularly urolithin A alone or in combination with EGCG, restore mitochondrial and synaptic health in Tau-induced toxicity models. These findings position mitophagy enhancement as a potential therapeutic approach requiring further validation in Alzheimer's disease.},
}

@article {pmid42276615,
year = {2026},
author = {Jain, V and Bharti, S},
title = {Environmental toxins, PFAS exposure, and brain metabolism: A new angle in Alzheimer's disease pathophysiology.},
journal = {International review of neurobiology},
volume = {186},
number = {},
pages = {107-144},
doi = {10.1016/bs.irn.2026.01.011},
pmid = {42276615},
issn = {2162-5514},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease with a complicated cause and effect, usually associated with amyloid-β plaques, tau pathology, and neuroinflammation. Recent research indicates that changes in brain energy metabolism play a crucial role in the progression of AD. Additionally, persistent environmental toxins, particularly per- and polyfluoroalkyl substances (PFAS), have attracted considerable attention due to their widespread occurrence, ability to accumulate in living organisms, and neurotoxic effects. This chapter explores the connection between PFAS exposure and metabolic dysfunction in the brain as a potential new factor in the etiology of Alzheimer's disease. This study explored the potential impacts of PFAS on insulin signaling, lipid homeostasis, glucose metabolism, mitochondrial dynamics, and brain energy supply. The epidemiological associations between PFAS exposure and cognitive impairment are also examined, along with the mechanisms underlying oxidative stress, neuroinflammation, and dysregulation of metabolic systems. Finally, prevention, management, therapeutic approaches, and the research gap in PFAS-induced neurotoxicity are explored. Findings from this study emphasize the need to incorporate environmental toxicology into the Alzheimer's disease metabolic model for the sake of future treatment and preventive efforts.},
}

@article {pmid42277155,
year = {2026},
author = {Wang, L and Knox, S and Lawson, AB and Mollalo, A},
title = {Agricultural pesticide use and Alzheimer's disease dementia prevalence across US counties in a mixed supervised-unsupervised analysis.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-55678-4},
pmid = {42277155},
issn = {2045-2322},
abstract = {Agricultural pesticide use represents one of the most geographically patterned environmental systems, yet most prior research has focused largely on individual compounds rather than correlated exposure regimes. We conducted a cross-sectional analysis using modeled pesticide application intensity and Alzheimer's Disease (AD) dementia prevalence at the county-level across the United States. Stability-based Elastic Net screening and clustering were used to identify exposure groupings, and associations with AD prevalence were estimated using adjusted regression models. Out of 462 total pesticides screened, 112 demonstrated high selection stability and were grouped into 25 exposure clusters. Twenty clusters were significantly associated with AD dementia prevalence (p<0.05). The strongest positive associations were observed for a soil fumigation/nematicide system, an herbicide-dominant vegetation control regime, and a neuroactive insecticide system. Neuroactive insecticides and soil-intensive treatment systems were disproportionately represented among positively associated clusters, whereas systems dominated by phenoxy- and photosystem II inhibiting herbicides were more frequently aligned with inverse gradients. The fully adjusted model explained 59% of between-county variance (baseline R[2] = 0.44). Findings suggest that pesticide mixtures are associated with geographic heterogeneity in AD dementia prevalence and warrant higher-resolution, longitudinal investigation.},
}

@article {pmid42277629,
year = {2026},
author = {Chang, Y and Li, H and Liu, X and Li, X and Liu, J and Song, J and Fu, H and Xu, X and Wang, Y and Wang, Q and Ren, N and Chen, J and Deng, X and Zhang, X and Zuo, L and Zhou, B and Sun, X and Li, Z and Cao, Y and Wu, R and Jia, J and Qian, H and Wang, R},
title = {Lecanemab Reduces Neuropsychiatric Symptoms and Related Regional Brain Amyloid Load in Early Alzheimer's Disease: A Preliminary Prospective Study.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {6},
pages = {e70974},
doi = {10.1002/cns.70974},
pmid = {42277629},
issn = {1755-5949},
support = {82371999//the National Natural Science Foundation of China/ ; 2021ZD0201804//the Ministry of Science and Technology of the People's Republic of China/ ; 24BJZ14//Health Special Research Projects/ ; //Novel Medical Technologies and Innovative Services of Chinese PLA General Hospital/ ; },
abstract = {AIM: This prospective study examined whether lecanemab was associated with changes in neuropsychiatric symptoms (NPS) and investigated their associations with cerebral amyloid burden in patients with early-stage Alzheimer's disease (AD).

METHODS: Fourteen eligible participants underwent amyloid positron emission tomography, magnetic resonance imaging, and neuropsychological assessments at baseline and following 6 months of lecanemab treatment. Neuropsychological assessments included the Clinical Dementia Rating, Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Hamilton Depression Rating Scale, Hamilton Anxiety Scale (HAMA), and Neuropsychiatric Inventory (NPI).

RESULTS: MMSE and MoCA remained stable, while amyloid burden decreased after 6 months of treatment (p < 0.05). HAMA, total NPI score, and NPI sub-scores for psychosis, hyperactivity, and apathy were also decreased (p < 0.05). Improvements in NPS were associated with lower amyloid burden in the hippocampus, amygdala, thalamus, inferior frontal gyrus (IFG), and anterior cingulate gyrus. These clinical improvements were associated with increased fractal dimension in the middle cingulate cortex and decreased sulcal depth in the IFG.

CONCLUSIONS: These findings suggest that, in early AD, lecanemab treatment may be associated with benefits beyond cognitive stabilization, including possible improvement in NPS, which may relate to amyloid clearance and structural changes in relevant brain regions.},
}

@article {pmid42277961,
year = {2026},
author = {Bonnar, O and Saadi, F and Sanchez-Mico, MV and Hanlin, LH and Vom Eigen, KA and Mumbi, N and Bacskai, BJ and Greenberg, SM and Holtzman, DM and van Veluw, SJ},
title = {Longitudinal multiphoton imaging of cerebral amyloid angiopathy in response to anti-ApoE4 immunotherapy in mice.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00957-x},
pmid = {42277961},
issn = {1750-1326},
support = {P01 AG078106/GF/NIH HHS/United States ; A2022051S//BrightFocus Foundation grant/ ; },
abstract = {BACKGROUND: There are no available treatments to halt or slow the progression of cerebral amyloid angiopathy (CAA), a disease neuropathologically characterized by the deposition of amyloid-β (Aβ) within the walls of the cerebrovasculature. Recently a novel therapeutic strategy has been described, targeting non-lipidated ApoE4 that co-deposits with Aβ, resulting in lower levels of Aβ across the brain. To understand the therapeutic potential for patients with CAA, we sought to determine if this global reduction in Aβ deposits corresponds to the active removal of existing aggregates in the vasculature and if so, whether this may improve vascular function over time.

METHODS: Cranial windows were implanted in 9-10-month-old 5xFAD mice expressing human APOE4 to facilitate chronic, unanesthetized imaging using in vivo multiphoton microscopy. Mice were treated weekly with anti-ApoE4 immunotherapy (HAE-4) or control IgG (50 mg/kg). Parenchymal and vascular Aβ burden as well as vascular function were measured in vivo before and during treatment. Post-mortem brains were assessed for CAA, parenchymal Aβ plaques and iron deposits. In a separate study, 5xFAD mice were treated with weekly HAE-4 or control IgG with the same doses of antibodies from 8 to 10 months of age in the absence of cranial windows.

RESULTS: Treatment with HAE-4 resulted in reduction of total Aβ plaque area post-mortem in mice and shrinkage of existing smaller plaques imaged with in vivo multiphoton microscopy. Vascular fibrillar Aβ under the cranial window conversely increased over time either with or without HAE-4 treatment and there was no treatment-associated improvement in vascular function in cortical arterioles in the areas measured in vivo. There was no evidence of hemorrhagic events linked to treatment, however there was significant immune cell activation. In 5xFAD mice treated without a cranial window, there was a reduction in plaques and CAA as previously described in HAE-4 vs. control treated mice.

CONCLUSIONS: Anti-ApoE4 immunotherapy, as shown previously, decreased the overall amount of Aβ. It also appeared to remove some existing plaque Aβ without measurable effects on vascular fibrillar Aβ deposits or vascular function in areas measured in vivo under a cranial window. The absence of treatment-associated hemorrhagic events may offer a comparative advantage relative to anti-Aβ immunotherapy.},
}

@article {pmid42278193,
year = {2026},
author = {Lourenço, KA and Dos Santos, MV and Araujo, AC and Guiguer, EL and Curi, R and Rocha, MG and Monteiro, ES and Yanaguizawa Junior, JL and Pithon-Curi, T and Quesada, K and de Abreu, LC and Marcondes, CO and Barbalho, SM and Valenti, VE and Miglino, MA},
title = {From Toxin to Therapy: Biomedical Applications of Bee Venom in Cancer, Diabetes, and Neurodegenerative Disorders.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114661},
pmid = {42278193},
issn = {1422-0067},
mesh = {Humans ; *Bee Venoms/therapeutic use/pharmacology/chemistry ; Animals ; *Neurodegenerative Diseases/drug therapy ; *Neoplasms/drug therapy ; *Diabetes Mellitus/drug therapy ; },
abstract = {Apitherapy is a complementary therapeutic approach based on the use of bee-derived products, particularly bee venom (BV), also known as apitoxin. Bee venom is a complex mixture of biologically active compounds, including peptides, enzymes, and biogenic amines, that exhibit diverse pharmacological activities. Major bioactive constituents such as melittin, apamin, adolapin, and phospholipase A2 have attracted increasing scientific interest due to their anti-inflammatory, antioxidant, antimicrobial, analgesic, and immunomodulatory properties. This review provides a comprehensive overview of the biological effects and therapeutic potential of bee venom in the management of chronic diseases, particularly diabetes, cancer, and neurological disorders. Evidence from experimental and clinical studies suggests that BV and its components can modulate multiple molecular pathways associated with oxidative stress, inflammation, apoptosis, and immune responses. These mechanisms contribute to potential benefits in glycemic control, tumor suppression, neuroprotection, and pain management. Additionally, bee venom has been investigated for its capacity to influence signaling pathways involved in cellular proliferation and survival, highlighting its potential as a complementary strategy in the treatment of complex diseases such as neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. Despite these promising therapeutic effects, the clinical use of BV remains limited due to safety concerns, particularly the risk of allergic reactions, systemic toxicity, and anaphylaxis. Recent advances in drug delivery systems and nanotechnology may help improve the safety and efficacy of BV-based therapies by enabling targeted delivery and controlled dosing. Overall, bee venom represents a promising source of bioactive compounds with potential applications in translational and integrative medicine; however, further well-designed clinical trials and mechanistic studies are necessary to establish its safety, efficacy, and long-term therapeutic value.},
}

Humans
*Bee Venoms/therapeutic use/pharmacology/chemistry
Animals
*Neurodegenerative Diseases/drug therapy
*Neoplasms/drug therapy
*Diabetes Mellitus/drug therapy

@article {pmid42278362,
year = {2026},
author = {Malenchini, M and Beretti, F and Gatti, M and Bertucci, E and Del Toro, E and Maraldi, T},
title = {Stem Cell-Derived Extracellular Vesicles Ameliorate the Neuron Mitochondrial Damage Induced by ROS-, LPS-Exposure: In Vitro Model of Neuron, Microglia, and Astrocyte Triple Co-Culture.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114834},
pmid = {42278362},
issn = {1422-0067},
mesh = {*Lipopolysaccharides/toxicity ; *Neurons/metabolism/drug effects ; *Mitochondria/metabolism/drug effects/pathology ; *Microglia/metabolism/drug effects ; *Reactive Oxygen Species/metabolism ; *Extracellular Vesicles/metabolism ; Coculture Techniques ; *Astrocytes/metabolism/drug effects/cytology ; Animals ; Humans ; Oxidative Stress/drug effects ; Hydrogen Peroxide ; Cell Survival/drug effects ; Cells, Cultured ; },
abstract = {Oxidative stress causes brain damage contributing to neurodegenerative and vascular diseases. In Alzheimer's disease (AD), elevated oxidative stress and mitochondrial damage are closely linked to misfolded protein accumulation. ROS also plays a major role in ischemic brain injury, particularly during reperfusion, impairing the blood-brain barrier and highlighting the association between vascular pathology and AD. To investigate perturbations in brain cells occurring in mixed dementia (AD combined with vascular dementia components), we used a triple culture system comprising neurons, astrocytes, and microglia and induced neuronal injury by combining LPS and H2O2 exposures. Cell viability assays revealed that neuronal death occurred mainly through apoptosis and DNA damage. In neurons and astrocytes exposed to LPS+H2O2, the expression of NADPH oxidase isoform 2, a major source of ROS, increased, along with FOXO3 and SOD2, a key mitochondrial ROS scavenger. Indeed, these changes were accompanied by altered mitochondrial morphology and integrity, as well as reduced neurite extension and thickness. The treatment with extracellular vesicles (EVs) derived from amniotic fluid stem cells was tested due to their rich content of antioxidant molecules. Interestingly, EVs reversed the negative effects of LPS+H2O2, suggesting the protective role against neuronal injury in vitro may be mediated by the EV-cargo.},
}

*Lipopolysaccharides/toxicity
*Neurons/metabolism/drug effects
*Mitochondria/metabolism/drug effects/pathology
*Microglia/metabolism/drug effects
*Reactive Oxygen Species/metabolism
*Extracellular Vesicles/metabolism
Coculture Techniques
*Astrocytes/metabolism/drug effects/cytology
Animals
Humans
Oxidative Stress/drug effects
Hydrogen Peroxide
Cell Survival/drug effects
Cells, Cultured

@article {pmid42278468,
year = {2026},
author = {Piekarczyk, N and Berezka, P and Domkowicz, K and Myślińska, D and Kaczor, JJ},
title = {Vitamin D3 and Dimethyl Fumarate Partially Restore Neurotrophic Signaling Without Altering Mitochondrial Integrity in the STZ-Induced Model of Sporadic AD.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114940},
pmid = {42278468},
issn = {1422-0067},
support = {531-D080-D248-25//Faculty of Biology/ ; },
abstract = {Alzheimer's disease (AD) is characterized by impaired neurotrophic support, oxidative stress, and metabolic dysfunction. Using the intracerebroventricular streptozotocin (ICV-STZ) rat model of sporadic AD, we investigated whether vitamin D3 (VitD3) and dimethyl fumarate (DMF), administered alone or in combination, modulate hippocampal neurotrophin-related signaling and redox balance. Animals were assigned to SHAM, STZ, VITD, DMF, and COMBO groups, representing control, ICV-STZ, VitD3-treated ICV-STZ, DMF-treated ICV-STZ, and combined VitD3 + DMF-treated ICV-STZ animals, respectively. Hippocampal neurotrophin processing (proBDNF and mature BDNF), downstream signaling (Akt and pAkt), IGF-1 content, mitochondrial oxoglutarate dehydrogenase (OGDH) content, citrate synthase (CS) activity, and glutathione peroxidase (GPx) activity were assessed. STZ administration showed a trend toward reduced mature BDNF content compared with the SHAM group (p = 0.07), whereas combined VitD3 and DMF treatment significantly increased mature BDNF content compared with the STZ group. The mature BDNF/proBDNF ratio was reduced in the STZ group compared with the SHAM group and tended to be higher in the COMBO group compared with the STZ group (p = 0.09). proBDNF content remained unchanged. IGF-1, pTrkB, total Akt, and pAkt content did not differ significantly between groups. The pAkt/Akt ratio showed a trend toward reduction in the STZ group compared with SHAM group (p = 0.09). GPx activity increased in the STZ group, while CS activity and OGDH content were not significantly altered. These findings indicate that STZ-induced neurodegeneration is characterized by redox-associated uncoupling of neurotrophic signaling rather than mitochondrial disruption. Combined VitD3 and DMF treatment partially modulated neurotrophic signaling, supporting a limited but measurable neuroprotective effect.},
}

@article {pmid42278518,
year = {2026},
author = {Ricci, S and Benuzzi, M and Fazzina, M and Cacialli, P},
title = {ZL006 Treatment Reduces Inflammation, Oxidative Stress, and Brain Aβ1-42 Accumulation and Rescues the Loss of PSD95 Synaptic Marker in Familial Alzheimer's Disease-Associated psen1-Deficient Zebrafish Model.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114992},
pmid = {42278518},
issn = {1422-0067},
support = {Cacialli-RFO2024//the Italian Ministry of University and Research (MIUR)/ ; },
abstract = {Familial Alzheimer's disease (FAD) is a rare form of Alzheimer's. FAD is mainly caused by one or multiple mutations in the genes encoding for amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), with the majority occurring in PSEN1. Despite extensive research in animal models and numerous promising treatment trials, there is still no curative treatment for FAD. Recently, ZL006 (Med Chem Express cat. Number HY-100456) was shown to reduce over-produced nitric oxide and oxidative stress in ischemic stroke and could protect neurons against Aβ1-42-induced neurotoxicity (in vitro study). With this in mind, we tested ZL006 at different doses (10 μM, 25 μM, 50 μM and 100 μM) in zebrafish embryo injected with ctrl-MO and psen1-MO, investigating the effects on pathological phenotype in vivo. We showed that ZL006 exposure suppresses inflammation, oxidative stress and accumulation of Aβ1-42 in psen1-MO. In conclusion, our study showed that ZL006 was able to ameliorate the pathological phenotype of psen1-morphant zebrafish embryos, supporting its potential as a candidate for further investigations in the context of FAD treatment.},
}

@article {pmid42278520,
year = {2026},
author = {Kassenova, A and Svirin, E and Sitdikova, K and Chaprov, K and Tsoy, A and Munter, J and Nurzhanov, A and Kuznetsova, M and Veremeyko, T and Deykin, A and Ponomarev, E and Strekalova, T and Askarova, S},
title = {Effects of Wheat Malt Extract on Molecular and Behavioral Markers in Aged APP/PS1 and Wild-Type Mice.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27114994},
pmid = {42278520},
issn = {1422-0067},
support = {AP23485236//Ministry of Science and Higher Education of the Republic of Kazakhstan/ ; Ref. No. 201223FD8829//The Faculty Development Competitive Research Grant Program, Nazarbayev Fund, Nazarbayev University/ ; FFSG-2024-0020//Scientific state assignment to the Centre for Collective Use IPAC RAS/ ; FZWG-2024-0003//The Scientific state assignment/ ; 101007642EU//The Marie Skłodowska-Curie PhytoApp within the European Union's Horizon 2020 research and innovation program (H2020-MSCA-RISE-2020)/ ; 101086453EU//The Marie Skłodowska-Curie Aqua-Synapse project within the European Union's Horizon 2020 research and innovation program (H2020-MSCA-RISE-2020)/ ; },
abstract = {Growing evidence suggests an important pathogenetic role of brain-specific gangliosides in the mechanisms underlying Alzheimer's disease (AD), the most common form of dementia. Nutritional strategies targeting ganglioside sialylation-for example, through agglutinin-mediated modulation-have therefore attracted increasing research interest. In particular, wheat malt extract (WME), a food-derived source of wheat germ agglutinin (WGA) with high affinity for gangliosides, may influence molecular pathways involved in AD pathogenesis. Twelve-month-old female APPswe/PS1E9 transgenic mice, a model of AD, and wild-type (WT) littermates received WME or tap water for three weeks. Behavioral performance was subsequently assessed. Amyloid plaque burden and astrocyte activation were evaluated using Congo red staining and GFAP immunoreactivity, respectively. Gene expression of selected AD markers in the brain was quantified by RT-qPCR. Aged WT mice exhibited robust, region-specific molecular responses to WME, including upregulation of activity-dependent and synaptic plasticity genes (Arc, Egr1, Bdnf, Syp), enhancement of metabolic and insulin-related signaling (Pgc1a, Sirt1, Igf1r, Irs2), increased Cldn5 expression, and reduced pro-inflammatory Il1β expression. APP/PS1 mice exhibited limited response to WME, suggesting more persistent transcriptional signatures of synaptic impairment, metabolic dysregulation, and neuroinflammation than in WT mice. We found no significant effects of WME treatment on amyloid plaque density and behavior in APP/PS1 mice. No effects on astrocyte activation were observed in either group. These findings demonstrate that dietary WME counteracts abnormal behaviors and molecular changes in neuron plasticity, metabolic, and vascular markers under conditions of normal aging but fails to improve the hallmarks of AD pathology. This highlights the potential of WGA-containing nutrients as a preventive nutritional approach targeting pathogenic mechanisms of aging and, potentially, AD pathology.},
}

@article {pmid42278547,
year = {2026},
author = {Pastén-Castrejón, NJ and Martínez-Orozco, H and Gutiérrez-Silerio, GY and Hernández-Montiel, HL and Maya-Arteaga, JP and Poblano-Paez, I and García-Solís, P and Díaz-Miranda, SY},
title = {Hippocampal, Microglial, Morphological, and Amyloid Profiles Following Thiamine Pyrophosphate Treatment in 3xTg-AD Mice.},
journal = {International journal of molecular sciences},
volume = {27},
number = {11},
pages = {},
doi = {10.3390/ijms27115022},
pmid = {42278547},
issn = {1422-0067},
mesh = {Animals ; *Microglia/metabolism/drug effects/pathology ; *Alzheimer Disease/drug therapy/metabolism/pathology/genetics ; *Thiamine Pyrophosphate/pharmacology ; Mice, Transgenic ; *Hippocampus/metabolism/drug effects/pathology ; Female ; Mice ; *Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) and chronic neuroinflammation, with microglia playing a central role in its pathogenesis. Alterations in microglial metabolism have been proposed to contribute to AD-related inflammatory responses and reduced Aβ clearance, suggesting that thiamine-dependent pathways may be relevant in this context. Thiamine pyrophosphate (TPP), the active form of vitamin B1, is essential for glucose metabolism and mitochondrial function; however, its association with microglial changes in AD remains unclear. In this study, 9-month-old female triple-transgenic AD (3xTg-AD) mice and non-transgenic controls (NoTg) received TPP (2.0 mg/mL) or saline as a vehicle for six weeks via osmotic pumps. Nesting, a hippocampus-dependent behavioral test, as well analyses of Aβ burden, microglial morphology, and the expression of genes related to metabolic and immune pathways were evaluated. Differences in nesting behavior between experimental groups were observed, but TPP treatment was not associated with an evident change in 3xTg-AD mice. In the subiculum and CA1 regions of the hippocampus of female 3xTg-AD mice exposed to TPP, a lower Aβ burden was observed, and morphological variations in microglia were detected in both groups (3xTg-AD and NoTg). Additionally, in the brain of the TPP-treated group, some changes in mRNA gene expression were recorded. Together, these findings describe hippocampal microglial and amyloid profiles following TPP treatment in 3xTg-AD mice and provide a basis for further investigation of thiamine-dependent pathways in AD-related neuroinflammatory contexts.},
}

Animals
*Microglia/metabolism/drug effects/pathology
*Alzheimer Disease/drug therapy/metabolism/pathology/genetics
*Thiamine Pyrophosphate/pharmacology
Mice, Transgenic
*Hippocampus/metabolism/drug effects/pathology
Female
Mice
*Amyloid beta-Peptides/metabolism
Disease Models, Animal

@article {pmid41998020,
year = {2026},
author = {Bisht, M and Gomes, MC and Bordon Sosa, FH and Mano, JF and Pandey, S and Ventura, SPM and Coutinho, JAP},
title = {Superbase ionic liquid mediated solubilization of curcumin for improved bioavailability and anticancer efficacy.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41998020},
issn = {2045-2322},
support = {REDE/1517/RMN/2005//Fundação para a Ciência e a Tecnologia/ ; PDF/2019/001024//Government of India/ ; },
abstract = {UNLABELLED: Curcumin is a promising natural drug for the treatment of various diseases ranging from cancer to Alzheimer’s. However, a major hindrance in its use as a drug is its low aqueous solubility, rapid degradation, and poor cellular uptake. In recent years, the use of ionic liquids (ILs) in biomedical applications has gained significant attention due to their unique properties and tunability. In this study, we demonstrate the capacity of the superbase ionic liquid (SBIL) 5-Methyl-1,5,7-triaza-bicyclo[4.3.0]non-6-enium acetate [mTBNH][OAc] to dissolve highly hydrophobic and water-insoluble curcumin. An optimized concentration of 4 mol.kg[-1] of SBIL was used to dissolve 3.5 mg.g[-1] of curcumin, resulting in a formulation (curcumin/SBIL) that could be easily dispersed in an aqueous medium. Compared to the aqueous solubility of curcumin alone, the curcumin/SBIL formulation exhibited almost an 8,000-fold increase in solubility, also demonstrating a reduction of ~ 60% of human triple-negative breast cancer epithelial cells (MDA-MB-231) viability with only 10 µg.mL[-1] of curcumin (the active compound), without any cytotoxic effects on non-tumorogenic mouse fibroblasts (L929). Our study presents a straightforward methodology for improving the solubility and bioavailability of curcumin, which holds promise for its clinical application as an effective anti-cancer drug.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-44082-7.},
}

@article {pmid42046101,
year = {2026},
author = {Andrews, D and Golchi, S and Collins, DL and , },
title = {A digital twin methodology using retrospective patient data for sample size reduction in Alzheimer's disease clinical trials.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42046101},
issn = {1758-9193},
support = {FRN 165921/CAPMC/CIHR/Canada ; RGPIN-2015-03633//Natural Sciences and Engineering Research Council of Canada/ ; FRN 165921/CAPMC/CIHR/Canada ; },
abstract = {BACKGROUND: Recruitment for Alzheimer’s disease randomized controlled trials (RCTs) is difficult and expensive. To reduce RCT sample sizes while maintaining high statistical power, our Digital Twin Trial (DTT) methodology combines an interpretable cognitive decline prediction model with prediction-powered inference. Unlike RCT sample size reduction techniques that maintain power by recruiting only patients likely to decline, prediction-powered inference is used within the data analysis stage of the trial and does not impose additional restrictions on participant eligibility.

METHODS: For DTT participants, our model identifies similar individuals (“Digital Twins”) from a retrospective trial-matched database and uses their cognitive scores to predict decline. Predictions adjust observed scores, reducing variance within treatment groups. We simulated 18-month DTTs and standard RCTs using mixed effects models of decline in Alzheimer’s Disease Neuroimaging Initiative subjects meeting lecanemab’s Phase 3 inclusion criteria.

RESULTS: Predicted and observed change in Clinical Dementia Rating Sum-of-Boxes correlated at r = 0.437. DTTs required 9.5–19.0% fewer subjects than standard RCTs to detect a simulated 25% decline-slowing drug effect at 0.9 power. DTT Type 1 error was consistent with 0.05.

CONCLUSIONS: DTTs could reduce clinical trial recruitment and cost burdens without imposing additional inclusion criteria, enabling efficient testing of new treatments in all populations who might benefit. Model interpretability will foster clinician and regulator trust in individualized prognoses. This transparency could help smooth the model’s translation to real trials and eventually the clinic, where it could help make prognoses and better evaluate treatment effects in individual patients.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02024-5.},
}

@article {pmid42266508,
year = {2026},
author = {Khajuria, P and Kour, D and Sharma, K and Singh, L and Banoo, R and Manhas, D and Ramajayan, P and Nandi, U and B Bharate, S and Ahmed, Z and Kumar, A},
title = {AMPK-mediated autophagy induction by bisdemethoxycurcumin attenuates senescence and amyloid pathology in 3xTg-AD mice.},
journal = {Autophagy reports},
volume = {5},
number = {1},
pages = {2675164},
pmid = {42266508},
issn = {2769-4127},
abstract = {Alzheimer disease (AD) pathology is accompanied by increased senescence and reduced levels of autophagy in the brain. We investigated whether pharmacologically inducing autophagy could alter the senescent phenotype and ameliorate AD pathology. We discovered that Bisdemethoxycurcumin (BDMC), a natural compound found in Curcuma longa, stimulates autophagy in primary astrocytes. We found that autophagy and senescence exhibit an inverse relationship in aging astrocytes, with increased expression of senescent proteins and downregulation of autophagic proteins. However, treatment of aged astrocytes with BDMC reversed the senescent phenotype by ameliorating the impaired autophagy. Interestingly, the senescent phenotype persisted when autophagy was downregulated by knockdown of AMPK. Additionally, BDMC-induced autophagy aided in the removal of amyloid beta (Aβ) that was administered externally to the astrocytes. Further, to validate these results in a mouse model of AD, we confirmed that BDMC significantly penetrates the blood-brain barrier (BBB) in mice. Therefore, we administered 50 and 100 mg/kg b.w. of BDMC to transgenic 3xTg-AD mice for two months. In their hippocampus, the Control 3xTg-AD animals showed more senescent cells and lower autophagy levels. In contrast, autophagic proteins were significantly upregulated while senescence indicators, such as senescence-associated secretory phenotype (SASP) proteins, were sharply downregulated in the brain of treated animals. We discovered that the hippocampus of treated mice had a significantly lower Aβ load. These molecular changes in the brain were ultimately reflected in the improved working memory and neuromuscular coordination behavior of mice treated with BDMC. This study warrants further evaluation of BDMC for the management of AD.},
}

@article {pmid42266879,
year = {2026},
author = {Amuthan, S and Senthilkumar, NC},
title = {Ensemble Deep Learning Denoising (EDLD) model and optimized OTSU segmentation for Alzheimer's disease diagnosis using MRI images.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1743818},
pmid = {42266879},
issn = {2624-8212},
abstract = {Diagnosing Alzheimer's disease (AD) is necessary to determine treatment options. AD categorization using machine learning (ML) relies on difficult, manually specified features. The most important stage in AD diagnosis is denoising to restore image stability and quality. An ensemble image denoising technique that combines Attention Guided Convolutional Neural Network (AGCNN), Adaptive Denoising Autoencoder (ADAE), and Gaussian Deep Belief Network (GDBN) improves image denoising performance. The hybrid AGCNN reduces noise and aligns along the global route by combining global and local characteristics. In ADAE, the encoder learns picture representations using convolutional layers (CLs) while the decoder uses deconvolutional layers. In addition, the GDBN extends the standard Deep Belief Network (DBN) to Gaussian Restricted Boltzmann Machines (RBMs). Ensemble learning selects the approach with the greatest Peak Signal-to-Noise Ratio (PSNR) to integrate learning outcomes. After separating the background from the foreground by calculating the variances within the two groups, OTSU determines the threshold that minimizes the weighted sum of the variances. Levy Grasshopper Optimization Algorithm (LGOA) optimizes threshold selection by mimicking grasshopper swarming. VGG16, the DCNN model, is pre-trained for Alzheimer's datasets. The results are Sensitivity (SEN -95.86%), specificity (SPC - 94.93%), precision (PPV - 94.55%), F1-score (F1 - 95.21%), accuracy (ACC -95.87%), and Area Under the Receiver Operating Characteristic Curve (AUC - 96.45%) assess system and method performance.},
}

@article {pmid42267529,
year = {2026},
author = {Lohnes, BJ and Myskova, A and Tyagi, A and Hartwig, UF and Poddar, NK},
title = {Rewiring mTOR signaling in Alzheimer's disease: emerging mTOR modulators beyond oncology.},
journal = {Bioscience reports},
volume = {46},
number = {6},
pages = {},
doi = {10.1042/BSR20260203},
pmid = {42267529},
issn = {1573-4935},
mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology/enzymology/metabolism ; *TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors ; Signal Transduction/drug effects ; Animals ; *MTOR Inhibitors/therapeutic use ; },
abstract = {While Alzheimer's disease (AD) is the most common cause of dementia, curative treatments remain unavailable. Despite distinct pathologies between AD and cancer, shared dysregulation of the PI3K-AKT-mTOR signaling pathway promotes both disease states. mTOR activity significantly contributes to AD hallmarks, including amyloid-beta production, tau hyperphosphorylation, and altered metabolism and autophagy through mTOR-mediated signaling and downstream targets such as BACE-1, GSK-3β, and AChE. Consequently, mTOR-modulating compounds, demonstrating promising results in oncology, present a viable strategy to potentially halt or reverse AD progression. This review discusses the potential application of 37 mTOR pathway-modulating compounds, many originally developed for cancer treatment, given their shared molecular targets. We systematically classified the compounds based on their origin as marine, plant-derived, structural analogs, and synthetic compounds. This framework reveals a fundamental trade-off, as the structural novelty and pleiotropic effects of natural products are often counterbalanced by poor pharmacokinetics, whereas the pharmacological precision of synthetic compounds is frequently limited by compensatory feedback loops. Furthermore, we analyze translational challenges, including balancing efficacy with toxicity, limitations in blood-brain barrier penetration, and the need for patient stratification using robust biomarkers. We conclude that the most promising therapeutic approach for AD involves synergistically combining natural products with rational synthetic design. Leveraging natural products as a source of novel chemical scaffolds and employing targeted synthetic engineering to overcome their pharmacokinetic limitations, this strategy moves beyond blunt pathway inhibition. Ultimately, this enables a highly nuanced modulation of the mTOR network, providing the basis for future preclinical and clinical drug development in AD.},
}

Humans
*Alzheimer Disease/drug therapy/pathology/enzymology/metabolism
*TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors
Signal Transduction/drug effects
Animals
*MTOR Inhibitors/therapeutic use

@article {pmid42267694,
year = {2026},
author = {Verma, M and Mohd Siddique, MU and Singh, NK},
title = {Corrigendum to: Neuroactive Phytoconstituents of Glycyrrhiza glabra for the Treatment of Alzheimer's Disease.},
journal = {Current topics in medicinal chemistry},
volume = {26},
number = {4},
pages = {422},
doi = {10.2174/156802662604260406111327},
pmid = {42267694},
issn = {1873-4294},
abstract = {It has come to our notice that in the published version of this article [1], the reference [96] was cited erroneously. The author has now corrected the reference sequence, and it is now cited as [95]. The revised section is provided below. The original article can be found online at https://www.eurekaselect.com/article/145138.},
}

@article {pmid42268277,
year = {2026},
author = {Agaltsov, MV},
title = {[Sleep-disordered breathing in older adults: clinical features and effects on the nervous system and mental health].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {5. Vyp. 2},
pages = {81-86},
doi = {10.17116/jnevro202612605281},
pmid = {42268277},
issn = {1997-7298},
abstract = {Obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder characterized by upper airway collapse, intermittent hypoxemia, intrathoracic pressure fluctuations, and sleep fragmentation. In older adults, the clinical presentation and consequences of OSA differ from those observed in middle-aged individuals, necessitating age-specific management strategies. This review discusses age-related aspects of OSA epidemiology and pathophysiology, as well as associations with neurological and psychiatric outcomes in later life. Evidence demonstrates that OSA prevalence increases with age in both sexes, with postmenopausal hormonal and metabolic changes further elevating risk in women. Aging is associated with reduced slow-wave sleep, increased sleep fragmentation, and upper airway structural alterations, all of which may affect respiratory event patterns and arousals. Notably, excessive daytime sleepiness may be less prominent in older adults despite clinically significant OSA. Emerging data link OSA in older adults to cognitive decline, Alzheimer's disease biomarkers, and heightened risk of cerebrovascular disorders, although research specifically targeting elderly populations remains limited. Positive airway pressure (PAP) therapy may enhance mood, daytime functioning, and certain cognitive outcomes; however, current evidence is constrained by small sample sizes, short follow-up, and adherence challenges. Diagnosis and management of OSA in older adults require age-appropriate clinical interpretation and further longitudinal and interventional studies to elucidate causal relationships and the effects of treatment on neurodegenerative and cerebrovascular outcomes.},
}

@article {pmid42268445,
year = {2026},
author = {Mohasel-Roodi, M and Nozari, M and Baghalishahi, M and Shamsara, A},
title = {The protective effects of dexmedetomidine via AMPK/SIRT1 pathway activation in a rat model of alzheimer's disease: evidence from preliminary findings.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42268445},
issn = {1573-4978},
mesh = {Animals ; *Dexmedetomidine/pharmacology/metabolism ; *Sirtuin 1/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Male ; Rats ; Rats, Wistar ; Disease Models, Animal ; *AMP-Activated Protein Kinases/metabolism ; Signal Transduction/drug effects ; Streptozocin ; *Neuroprotective Agents/pharmacology ; Neurons/drug effects/metabolism ; Hippocampus/metabolism/drug effects ; },
abstract = {BACKGROUND: Metabolic dysfunction and impaired energy signaling play critical roles in Alzheimer's disease (AD). The AMP-activated protein kinase (AMPK) / sirtuin-1 (SIRT1) pathway is a key regulator of neuronal energy homeostasis and survival. Dexmedetomidine (Dex), a selective α -2 adrenergic receptor agonist, has shown neuroprotective effects in acute neurological injury and energy homeostasis; however, its efficacy in metabolically driven AD models remains unclear.

METHODS: Forty-two adult male Wistar rats were randomly assigned to seven groups: control, sham, STZ, sham + Dex 25, STZ + Dex 25, STZ + Dex 50, and STZ + Dex 100 (n = 6/group). Sporadic AD was induced by bilateral intracerebroventricular injections of streptozotocin (STZ, 3 mg/kg) on days 1 and 3. Dex was administered intraperitoneally at doses of 25, 50, or 100 µg/kg following STZ injection. Hippocampal neuronal injury was assessed by Nissl staining, and AMPK and SIRT1 protein levels were evaluated using Western blot analysis 30 days after STZ administration.

RESULTS: STZ administration significantly increased neuronal injury in the hippocampal CA1 region and markedly reduced AMPK and SIRT1 expression compared with control and sham groups (p < 0.05-0.001). Dex treatment at all doses significantly attenuated CA1 neuronal damage, with the most pronounced histological protection observed at 25 µg/kg (p < 0.001). In parallel, Dex reversed STZ-induced downregulation of AMPK and SIRT1, with maximal molecular upregulation observed at 100 µg/kg (p < 0.05).

CONCLUSIONS: Dex mitigates STZ-induced hippocampal neurodegeneration, at least in part, through modulation of the AMPK/SIRT1 signaling pathway. These findings support the therapeutic potential of Dex in metabolically driven models of sporadic AD.},
}

Animals
*Dexmedetomidine/pharmacology/metabolism
*Sirtuin 1/metabolism
*Alzheimer Disease/drug therapy/metabolism
Male
Rats
Rats, Wistar
Disease Models, Animal
*AMP-Activated Protein Kinases/metabolism
Signal Transduction/drug effects
Streptozocin
*Neuroprotective Agents/pharmacology
Neurons/drug effects/metabolism
Hippocampus/metabolism/drug effects

@article {pmid42268464,
year = {2026},
author = {Mishra, H and Mishra, MK},
title = {Advances in anti-tau therapeutics for alzheimer's disease: immunotherapy, gene modulation, and combination approaches.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42268464},
issn = {1573-4978},
abstract = {Tau protein abnormalities are more detrimental to neurocognitive function and behaviour than amyloid plaque formation in patients affected by Alzheimer's Disease (AD) - the most common cause of dementia worldwide. Pathologically, tau misfolding, neurofibrillary tangle formation, hyper phosphorylation, and dissociation from microtubules lead to synaptic dysfunction and neuron death. With this understanding, tau is now a major therapeutic target; there is a growing research effort to assess immunotherapy, kinase inhibitors, and tau aggregation inhibitors, and evidence suggests that combination therapies may have synergistic effects. Although there are many challenges remaining, including poor late-stage trial efficacy and limited therapeutic access through the blood-brain barrier, the preliminary results from early preclinical and clinical studies suggest that tau pathology can be reduced and neuronal function improved. Additionally, RNA interference, antisense oligonucleotides, and other gene-based therapies are under investigation. Overall, tau-directed treatments show promise for the treatment of AD, with particular optimism about improvements in delivery systems and combination therapies that will lead to substantial therapeutic benefits and improved quality of life for patients with AD.},
}

@article {pmid42268602,
year = {2026},
author = {Moore, GJ and Bose, N and Henter, ID and Manji, HK},
title = {The 25-Year Evolution of Lithium as a Disease-Modifying Agent in Dementia: A Narrative Review.},
journal = {JAMA psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamapsychiatry.2026.1296},
pmid = {42268602},
issn = {2168-6238},
abstract = {IMPORTANCE: Lithium, a long-established cornerstone therapy for bipolar disorder, is a biologically plausible disease-modifying agent for neurodegenerative disorders, including mild cognitive impairment (MCI) and Alzheimer disease (AD).

OBSERVATIONS: Rather than targeting a single pathology like amyloid or tau, lithium acts across multiple cellular resilience pathways. Chronic lithium exposure induces the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), enhances brain-derived neurotrophic factor (BDNF) signaling, inhibits glycogen synthase kinase-3β (GSK-3β), stabilizes mitochondrial function, and reduces oxidative stress. These convergent mechanisms promote neuronal survival and synaptic integrity. In humans, proton magnetic resonance spectroscopy studies found that lithium increased N-acetylaspartate levels, consistent with improved neuronal viability, and structural magnetic resonance imaging (MRI) studies found that lithium preserved gray matter and/or reversed illness-related atrophy in hippocampal and corticolimbic regions. In addition, extensive evidence demonstrates that low-dose lithium (approximately 0.3mM)-significantly lower than traditional psychiatric doses (0.6-1.0mM)-exerts robust neurotrophic and neuroprotective effects. Preclinical models have found that these concentrations stimulate hippocampal neurogenesis, promote structural plasticity, and protect against proteotoxic injury. Furthermore, epidemiological studies have associated cumulative lithium exposure with reduced dementia risk, and early randomized clinical trials in MCI suggest cognitive stabilization and favorable tau biomarker changes at low, well-tolerated doses. The recent repletion hypothesis suggests that lithium may also function as a physiological trace element, but these findings await independent replication.

CONCLUSIONS AND RELEVANCE: These convergent data support a prospective clinical trial of low-dose lithium orotate to slow disease progression in MCI. Such an approach would prioritize established neuroprotective mechanisms while potentially mitigating the kidney and thyroid risks associated with higher-dose carbonate formulations. If low-dose lithium can indeed meaningfully alter disease trajectory, it would represent a much-needed, accessible, and inexpensive treatment that may be especially relevant in low- and middle-income countries.},
}

@article {pmid42269217,
year = {2026},
author = {Chae, HJ and Kwon, H and Son, SR and Moon, S and Park, AY and Bae, HJ and Jang, DS and Kim, DH},
title = {Fukinolic acid facilitates toxic amyloid-β oligomerization and exacerbates synaptic dysfunction.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {200},
number = {},
pages = {119619},
doi = {10.1016/j.biopha.2026.119619},
pmid = {42269217},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) aggregates that induce synaptic dysfunction and neuronal loss. Among the various Aβ species, soluble oligomers are considered the most neurotoxic forms and play a critical role in AD progression. Fukinolic acid (FA), a polyphenolic compound isolated from medicinal plants, has been reported to possess antioxidant and anti-inflammatory activities; however, its effects on Aβ aggregation have not been investigated. In the present study, we investigated whether FA modulates Aβ aggregation and synaptic dysfunction. Molecular docking analysis suggested that FA directly interacts with Aβ monomers at aggregation-prone regions. Consistent with this prediction, FA facilitated the formation of toxic Aβ oligomers and enhanced Aβ-induced neuronal cytotoxicity. The potentiation of Aβ toxicity by FA was abolished by an N-methyl-D-aspartate (NMDA) receptor antagonist, indicating the involvement of NMDA receptor-dependent signaling. Electrophysiological recordings showed that FA exacerbated Aβ-induced long-term potentiation (LTP) impairment in hippocampal slices without affecting basal synaptic transmission. In addition, FA administration increased Aβ deposition and reduced neuronal viability in the hippocampus of 5XFAD mice. FA treatment showed non-significant trends toward reduced hippocampal LTP and spontaneous alternation in the Y-maze test, indicating that further studies are required to determine whether FA affects synaptic and cognitive function in vivo. These findings suggest that FA promotes toxic Aβ oligomer formation and may aggravate Aβ-associated synaptic impairment through NMDA receptor-dependent mechanisms, highlighting the importance of evaluating the effects of natural compounds on Aβ pathology in AD.},
}

@article {pmid42270143,
year = {2026},
author = {Semiz, M and Millien, E and Simoes Loureiro, I},
title = {Comparing approaches to treating anomia in early Alzheimer's disease: Network model-based method vs. embodied cognition method.},
journal = {Neuropsychological rehabilitation},
volume = {},
number = {},
pages = {1-29},
doi = {10.1080/09602011.2026.2685294},
pmid = {42270143},
issn = {1464-0694},
abstract = {Semantic memory is affected early on in Alzheimer's disease (AD), leading to language difficulties such as anomia. Defined as the inability to find words during speech, anomia constitutes a real obstacle to the quality of life of AD patients. The aim of this research is to study the benefits of two treatment methods: the ESFA (Elaborated Semantic Feature Analysis) method, based on abstractive network models of semantic memory, and the TERM (Treatment by Embodied Reactivation of Memory) method, a new sensorimotor stimulations therapy based on the theory of embodied cognition. 19 patients with early-stage AD (MMSE ≥20/30) were distributed into two groups: ESFA group (N = 10, 7 women and 3 men; mean age = 82.7, SD = 4.52) and TERM group (N = 9, 8 women and 1 man; mean age = 81.78, SD = 7.26). Groups were equal, and comparisons were possible. While the ESFA method allows a broad improvement in both trained (W = -2.809; p = .005) and untrained (W = -2.194; p = .028) items, the TERM method seems to lead to an item-centered effect (W = -2.668; p = .008). Moreover, only with the TERM method, the benefits seem to be maintained (W = -1.715; p = .086). Further studies are still needed to further investigate the benefits of these two interesting methods.},
}

@article {pmid42271174,
year = {2026},
author = {Sdougkou, K and Rekka, E and Papagiannopoulou, D},
title = {Synthesis and Evaluation of Novel Cinnamic Acid Hybrids With Antiacetylcholinesterase, Antioxidant, and Anti-Inflammatory Properties.},
journal = {ChemMedChem},
volume = {21},
number = {11},
pages = {e70343},
doi = {10.1002/cmdc.70343},
pmid = {42271174},
issn = {1860-7187},
abstract = {Alzheimer's disease, one of the most widespread neurodegenerative disorders, is known for its multifactorial nature that makes it challenging to treat. In the present work, hybrid molecules were designed and synthesized combining the anti-acetylcholinesterase (AChE) activity of donepezil with the antioxidant and/or anti-inflammatory activity of selected cinnamic acids. In particular, the new derivatives were conjugated by Steglich esterification or amidation of suitable benzylpiperazine/piperidine moieties with ferulic, sinapic, 3,4-dimethoxycinnamic acids. All new molecules were evaluated for their activity in terms of AChE inhibition, while molecules that carried a phenolic group were also evaluated for their ability to inhibit lipid peroxidation. A representative group of compounds were studied in vivo for their anti-inflammatory activity with very encouraging results in paw-induced edema in mice. The 3,4-dimethoxycinnamic and sinapic acid esters with a two-carbon linker exhibited the strongest inhibition of AChE with nanomolar values of IC50. In addition, the sinapic esters demonstrated the highest antioxidant and anti-inflammatory activity. Thus, the above results indicate that the new sinapic acid derivatives based on donepezil combine anti-AChE, anti-inflammatory, and antioxidant activities, which warrant their further evaluation as new lead compounds in the treatment of related neurodegenerative diseases.},
}

@article {pmid42272624,
year = {2026},
author = {Pham, D and O'Brien, C and Florez-Bhandari, J and Faulstich, N and Ojo, T and Aloi, S and Goodwin, R and Roley, L and Nathaniel, SI and Nathaniel, TI},
title = {Risk factors associated with cancer and metabolic encephalopathy in Alzheimer's disease patients.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1810937},
pmid = {42272624},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) frequently coexists with risk factors that modify its clinical course. The combined presence of cancer and metabolic encephalopathy (ME) in AD represents a particularly vulnerable and understudied phenotype. We investigated whether cancer-associated risk profiles differ between AD patients with and without metabolic encephalopathy.

METHODS: We used multivariate logistic regression to identify clinical, vascular, pulmonary, neurocognitive, psychiatric, and treatment-related factors distinguishing (i) AD patients with metabolic encephalopathy with and without cancer (AD + ME ± C) and (ii) AD patients without metabolic encephalopathy with and without cancer (AD - ME ± C). Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were used to identify risk factors and phenotype-specific associations.

RESULTS: Of the total cohort, 10,516 patients had metabolic encephalopathy, and 118,253 did not. Cancer coexistence was present in 146 AD + ME patients and 1,167 AD - ME patients. Among AD + ME patients, cancer was strongly associated with cerebrovascular accident (OR = 3.47, 95% CI 2.16-5.59), secondary dementia (OR = 9.89, 95% CI 3.26-29.98), mild cognitive impairment (OR = 5.20, 95% CI 1.98-13.27), chronic obstructive pulmonary disease (OR = 7.66, 95% CI 5.20-11.29), and SSRI use (OR = 3.27, 95% CI 2.21-4.87). In contrast, memantine, buspirone, and valproate were associated with AD + ME without cancer. Among AD-ME patients, cancer was associated with dyslipidemia, peripheral vascular disease, congestive heart failure, arteriosclerosis, COPD, and cutaneous ulcers, reflecting chronic systemic illness.

CONCLUSION: Metabolic encephalopathy was associated with a different clinical profile in cancer-associated AD. Patients with ME exhibited increased systemic and neurologic vulnerability (e.g., vascular comorbidity and frailty indicators) rather than differences in baseline cognitive severity alone.},
}

@article {pmid42273369,
year = {2026},
author = {Offerdahl, JEV and Mor, DE},
title = {Toward common treatment strategies: convergent proteinopathies and mitochondrial dysfunction in Alzheimer's and Parkinson's diseases.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1846384},
pmid = {42273369},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent neurodegenerative disorders (ND) globally, disproportionately affecting the elderly population. Traditionally viewed as distinct diseases, AD is defined by symptoms of cognitive impairment and dementia with amyloid-β and tau protein pathologies, while PD is defined by motor symptoms and eventual dementia with α-synuclein (α-syn) protein pathology. However, these pathologies are not unique to either disease, with a large fraction of AD patients displaying α-syn inclusions and PD patients displaying abnormal tau. Emerging evidence indicates that pathological tau and α-syn not only frequently coexist in AD and PD, but may engage in synergistic interactions that promote mitochondrial dysfunction, accelerate neurodegeneration, and worsen cognitive decline in both disorders. This review aims to provide both the prevailing views of AD and PD, as well as a detailed discussion of their commonalities with a focus on how tau and α-syn toxicities intersect at the mitochondrial level. Common features of mitochondrial impairment in AD and PD are discussed, including complex I deficiency, oxidative stress, impaired axonal transport, altered mitochondrial dynamics, and mitochondrial DNA damage. While prior reviews have often examined AD and PD independently, this review specifically focuses on the convergent and potentially synergistic interactions between tau and α-syn at the level of mitochondrial dysfunction, highlighting a shared mechanistic framework that may inform unified therapeutic strategies. By studying and understanding the mutual mechanisms underlying neurodegeneration in AD and PD, common treatment strategies can be identified.},
}

@article {pmid42273802,
year = {2026},
author = {Raket, LL and Lu, M and Evans, CD and Zimmer, JA and Sparks, J and Collins, EC and Shcherbinin, S and Wang, H and Nery, ESM and Epelbaum, S and Dell'Agnello, G and Brooks, DA and Sims, JR and Mintun, MA},
title = {Donanemab treatment effect by baseline tau burden and disease severity: Observations from the TRAILBLAZER-ALZ 2 trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71577},
pmid = {42273802},
issn = {1552-5279},
support = {//Eli Lilly and Company/ ; },
abstract = {INTRODUCTION: Clinical trials indicate that disease-modifying therapies can slow clinical decline in Alzheimer's disease (AD), with earlier initiation associated with greater slowing.

METHODS: In the TRAILBLAZER-ALZ 2 trial, the treatment effect of donanemab on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score was assessed across disease stages defined by baseline tau PET, plasma P-tau217 levels, or predicted disease progression.

RESULTS: Donanemab-mediated slowing of disease progression occurred across baseline tau PET and plasma P-tau217 levels. Participants with lower baseline tau PET and P-tau217 showed greater slowing with donanemab versus placebo. Modeling CDR-SB scores indicated that earlier treatment (at the 25[th] percentile of baseline Predicted disease progression) delayed disease progression by 60% over 76 weeks, compared to 33% and 17% at the 50[th] and 75[th] percentiles.

DISCUSSION: Donanemab benefited participants with early symptomatic AD across clinical and pathological severities, with the greatest slowing in those treated earlier.

CLINICALTRIALS: gov Identifier: NCT04437511.},
}

@article {pmid42274471,
year = {2026},
author = {Yang, Y and Ma, Y and Wang, P and Guan, PP},
title = {Triptolide Reduces Cholesterol Synthesis and Alleviates Neuroinflammation by Inhibiting CD33 in Alzheimer's Disease Development and Progression.},
journal = {Biology},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/biology15110818},
pmid = {42274471},
issn = {2079-7737},
support = {D2402007//Shenzhen Medical Research Fund/ ; GDRC202404//Natural Science Foundation of Top Talent of SZTU/ ; 2025ZDZX2061//Special projects in key areas of ordinary universities in Guangdong Province/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which has recently been found to be closely associated with neuroinflammation. As an anti-inflammatory drug, triptolide (TP), a natural diterpenoid from Tripterygium wilfordii, was selected in the current study for treating PS19 (tau[P301S] transgenic) mice, tauopathy AD mice. In addition, we have previously found that TP had the ability to reduce the level of cholesterol. However, the roles and mechanisms of TP in the above processes are not clear. To this end, we found that elevated cholesterol in serum and brain tissues upregulated the expression of apolipoprotein E (APOE) and sialic acid-binding Ig-like lectin 3 (CD33), leading to the activation of SH2-containing protein tyrosine phosphatase 1 (SHP-1). The activation of SHP-1 inhibits the signaling pathways of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 6 (STAT6), which results in inhibition of the M2 polarization of microglia, which exacerbates neuroinflammation and cognitive decline in high-cholesterol diet (HCD)-fed mice. Conversely, TP treatment significantly inhibited the hepatic sterol regulatory element-binding protein 2 (SREBP2)/3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) pathway, which reduced the cholesterol levels in the serum and brain. By depressing the levels of cholesterol, the axis of CD33 and SHP-1 was suppressed, which resulted in restoration of the activity of JAK1 and STAT6 pathways, leading to the transition of microglia from the M1 to the M2 phenotype. Of note, these observations demonstrate that TP alleviates the cognitive impairment of PS19 mice via depressing neuroinflammation. Altogether, our results revealed the mechanisms of TP in treating AD via CD33/SHP-1/JAK1/STAT6 pathways in a cholesterol-dependent manner.},
}

@article {pmid42274838,
year = {2026},
author = {Lior, N and Anna, P and Roni, H and Daniel, MM and Dan, F and Ronit, PK},
title = {APOE4-Expressing Astrocytes Exhibit Parkinson's Disease-Related Pathology.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42274838},
issn = {1559-1182},
abstract = {Parkinson's disease (PD) is characterized by motor symptoms that are mainly attributed to the progressive loss of dopaminergic neurons of the substantia nigra (SN). It is also characterized by abnormal inclusion vesicles, termed Lewy bodies (LBs), enriched with α-synuclein aggregates that may induce inflammation and neurotoxicity. The possibility that factors involved in other neurodegenerative diseases also affect PD-related pathologies, such as α-synuclein uptake, was examined. The apoe4 allele is a major genetic risk factor for Alzheimer's disease (AD) and has also been suggested to be involved in PD. Here, we examined the effects of APOE isoform expression on α-synuclein uptake and autophagy in astrocytes expressing the apoe3 or apoe4 alleles. Using multiple autophagy manipulations (EBSS, chloroquine, and rapamycin treatments), we found that α-synuclein uptake and autophagy readouts differ between APOE3 and APOE4 astrocytes, supporting a functional link between autophagy status and α-synuclein levels. Astrocytes expressing APOE4 exhibit reduced uptake of α-synuclein and reduced autophagy. Moreover, α-synuclein treatment inhibits autophagy mainly in APOE3-expressing cells. Additional experiments showed that the autophagy inhibitor chloroquine reduced α-synuclein uptake in APOE3 astrocytes but not in APOE4 astrocytes, while the autophagy enhancer rapamycin increased α-synuclein uptake in APOE4-expressing astrocytes. In addition, we found that Toll-like receptor 2 (TLR2) levels are elevated at both the mRNA and protein levels in APOE4-expressing astrocytes, whereas α-synuclein increased only TLR2 mRNA levels in APOE3-expressing astrocytes. Using the neurotoxin 1-methyl-4-phenylpyridinium (MPP[+]), we found that it affects cell growth in both APOE3 and APOE4-expressing astrocytes. MPP[+] treatment also reduced autophagy which was partially corrected by rapamycin. Taken together, these findings show that in astrocytes, APOE4 impairs α-synuclein uptake, which was emended by rapamycin and α-synuclein inhibits autophagy mainly in APOE3. These findings suggest that autophagy-targeting strategies can modulate astrocyte α-synuclein uptake; however, given the observed reductions in astrocyte cell number following rapamycin treatment, further optimization or examination of alternative autophagy modulators is needed.},
}

@article {pmid42026585,
year = {2026},
author = {Choi, H and Hong, SB and Kim, Y and Joung, H and Choi, Y and Cha, J and Park, JY and Lee, YS and Choi, H and Han, JW and Kim, KH and Shin, CH and Lee, DY and Mook-Jung, I},
title = {Tryptophan-kynurenine metabolic reprogramming along the gut-brain axis alleviates Alzheimer's pathology.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {42026585},
issn = {1742-2094},
support = {RS-2022-KH128705//Korea Dementia Research Center/ ; RS-2020-KH106747//Korea Dementia Research Center/ ; RS-2023-00273634//National Research Foundation of Korea/ ; },
abstract = {UNLABELLED: The gut–brain axis influences neuroinflammation and metabolic homeostasis in Alzheimer’s disease (AD). Disruption of gut microbiota and barrier function promotes amyloid and tau pathology via immune and metabolic dysregulation. In this study, Limosilactobacillus fermentum SRK414 (SRK414) was orally administered to ADLP[APT] mice, resulting in reduced Aβ and tau pathology and improved cognition. Multi-omics analysis revealed that SRK414 altered gut microbial composition and increased hippocampal kynurenic acid (KYNA), a metabolite linked to neuroimmune regulation. Increased hippocampal KYNA was associated with metabolic changes consistent with enhanced neuronal fatty acid oxidation, reduced lipid accumulation, and suppressed microglial activation, suggesting improved hippocampal homeostasis. In vitro studies further showed that KYNA attenuated tau-related and inflammatory phenotypes. These findings support a link between gut microbial modulation and brain resilience, and suggest that KYNA may contribute to the neuroprotective effects associated with SRK414 treatment. This study highlights metabolites modulated by SRK414 administration as potential mediators of microbiota-based therapeutic effects in AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03796-1.},
}

@article {pmid42255966,
year = {2026},
author = {Li, Y and Zhao, Y and Yang, A and Wang, Y and Xin, J and Chen, Y and Xing, X and Liu, F and Zou, Y and Zhao, W and Song, L and Gong, T and Wang, G},
title = {Lecanemab treatment modulates brain volume and cerebrospinal fluid pathways in early Alzheimer's disease: Insights from longitudinal magnetic resonance imaging.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70348},
pmid = {42255966},
issn = {2352-8729},
abstract = {INTRODUCTION: Lecanemab provides clinical benefits in early Alzheimer's disease (AD), but its longitudinal effects on brain structure, particularly cerebrospinal fluid (CSF) compartments, remain unclear. This study examined treatment-associated structural changes using longitudinal MRI.

METHODS: Thirty-one patients with mild cognitive impairment (MCI) or early AD underwent baseline and follow-up (1-7 months) 3D T1-weighted MRI during lecanemab treatment. Gray matter (GM), ventricular, choroid plexus (CP), and perivascular space (PVS) volumes were quantified. Longitudinal changes were analyzed with paired tests and linear mixed-effects models (LMMs).

RESULTS: Significant GM volume reductions were observed in AD-vulnerable regions (hippocampus, entorhinal cortex, precuneus), with increased CSF volumes. PVS volume showed a modest, non-significant decline. CP enlargement was associated with ventricular expansion.

DISCUSSION: Lecanemab treatment was associated with coordinated parenchymal and CSF-related structural changes. CP and PVS dynamics may represent potential MRI-based markers for monitoring early AD.},
}

@article {pmid42256567,
year = {2026},
author = {Rus Prelog, P and Zupan, M and Kovačič, A and Frol, S and Gregorič Kramberger, M},
title = {Amyloid-targeting treatment in Alzheimer's disease and concomitant antiplatelets: a clinical gray zone?.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1814289},
pmid = {42256567},
issn = {1664-2295},
}

@article {pmid42256792,
year = {2026},
author = {Dong, Y and Bai, X and Chen, Y and Wang, J and Cui, Q and Fan, L and Li, S and Qiu, Y},
title = {Timosaponin B-II attenuates hemorrhagic transformation-driven acceleration of alzheimer disease-related pathology after ischemic stroke.},
journal = {Biochemistry and biophysics reports},
volume = {46},
number = {},
pages = {102654},
pmid = {42256792},
issn = {2405-5808},
abstract = {Hemorrhagic transformation (HT) is a major complication of reperfusion therapy after ischemic stroke, but its impact on Alzheimer disease (AD) progression remains unclear. In this study, we used an early-stage APP/PS1 mouse model and found that HT following transient middle cerebral artery occlusion(tMCAO) aggravated cognitive impairment and promoted AD-like pathological changes, which were markedly attenuated by Timosaponin B-II (TB-II) treatment. TB-II effectively alleviated HT following tMCAO(tMCAO/HT)-induced cognitive and recognition memory deficits in APP/PS1 mice and reduced hippocampal Aβ42 production. In vitro, TB-II pretreatment reversed oxygen-glucose deprivation/reoxygenation (OGD/R) and hemin-induced increases in Aβ42 production and apoptotic propensity, as well as decreases in mitochondrial membrane potential and cell viability in N2a/APPswe cells. Mechanistically, TB-II activated NRF2, which in turn indirectly modulating GSK-3β-mediated APP phosphorylation and negatively regulated BACE1 transcription through binding promoter binding, ultimately suppressing amyloidogenic processing. Together, our findings suggest that TB-II may serve as a potential therapeutic agent against HT-associated acceleration of AD-like pathology after ischemia-reperfusion.},
}

@article {pmid42257639,
year = {2026},
author = {Kleiner, G and Lang, AE},
title = {Paratonia in Advanced Dementia: Deconstructing Scientific, Regulatory, and Health System Barriers to Botulinum Toxin A (BoNT-A) Treatment of Involuntary Muscle Resistance.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {106285},
doi = {10.1016/j.jamda.2026.106285},
pmid = {42257639},
issn = {1538-9375},
abstract = {Paratonia, a movement disorder characterized by involuntary muscle resistance, affects nearly all people with advanced dementia and contributes to caregiver burden, hygiene complications, pressure injuries, and pain. With Alzheimer's disease and related dementias affecting 7.2 million Americans and projected to reach nearly 14 million by 2060, the clinical impact of paratonia will expand proportionally. Because the involuntary muscle resistance of paratonia is frequently misinterpreted as deliberate noncompliance, individuals may receive inappropriate pharmacologic management rather than targeted treatment of the underlying movement disorder. No treatments are currently approved specifically for paratonia-induced muscle postures. Passive motion therapy, which the Centers for Medicare & Medicaid Services quality standards promote for contracture prevention in nursing homes, showed no benefit for paratonia in a randomized controlled trial of individuals with advanced dementia. Furthermore, passive movement therapy may paradoxically reinforce abnormal motor patterns by triggering increased involuntary resistance, the defining feature of paratonia. Botulinum toxin A, in therapeutic use since 1989, with Food and Drug Administration approval, is an established treatment for post-stroke spasticity and cervical dystonia. These conditions, like paratonia, arise from distinct central nervous system pathologies but share a peripheral manifestation of involuntary sustained muscle contraction. Preliminary clinical evidence suggests potential safety and efficacy for paratonia-induced muscle postures. Despite the therapeutic rationale and preliminary evidence for safety and efficacy, pharmaceutical companies have not pursued regulatory approval for the paratonia indication. This article examines barriers to clinical development, including scientific uncertainties, knowledge gaps, infrastructure limitations, therapeutic nihilism, policy barriers, and pharmaceutical industry considerations. We propose coordinated stakeholder action across research, education, policy, and regulatory domains to establish pathways toward further research and, if warranted, clinical implementation.},
}

@article {pmid42259049,
year = {2026},
author = {Wang, C and Song, X and Chen, D and Su, J and Wang, Y and Huang, C and Wei, W},
title = {Gold-nanocube-based SERS sensor for accurate detection of Alzheimer's disease biomarkers: Aβ42 and MAO-B.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {362},
number = {},
pages = {128185},
doi = {10.1016/j.saa.2026.128185},
pmid = {42259049},
issn = {1873-3557},
abstract = {Considering the irreversible nature of Alzheimer's disease (AD), early diagnosis is of great importance for AD treatment. Both β-amyloid (Aβ) and monoamine oxidase B (MAO-B) are potential biomarkers for AD. This study developed a surface-enhanced Raman scattering (SERS) sensor using gold-nanocube (OX-AuNCs) to detect Aβ42 and MAO-B. OX-AuNCs, a type of gold-nanocube with open gaps, achieved a Raman enhancement factor of 8.99 × 10[8] due to numerous hot spots. The specific affinity between Thioflavin T (ThT) and Aβ42 inhibits ThT's intramolecular rotation, reducing its SERS signal. This reduced signal showed a linear correlation with Aβ42 concentrations from 66.70 pM to 0.20 μM, achieving a limit of detection (LOD) at 44.30 pM, while also distinguishing different aggregation levels of Aβ42. Interestingly, SERS intensity of phenethylamine (PEA) also decreased significantly when interacting with MAO-B. A linear relationship was found between the change in PEA intensity and MAO-B concentration (0.01-20.00 μg mL[-1]), yielding an LOD of 5.00 ng mL[-1]. The proposed SERS sensor effectively detected two potential AD biomarkers, Aβ42 and MAO-B, in artificial cerebrospinal fluid (ACSF) and human serum with satisfactory recovery rates, respectively. These results show promise for clinical diagnosis and drug screening for AD.},
}

@article {pmid42259474,
year = {2026},
author = {Ma, Z and Yang, Z and Xiao, Z and Huang, B and Wang, X},
title = {Unveiling the Multi-Target Mechanisms of Zuo Gui Wan in Alzheimer's Disease: An Integrated Study Combining Network Pharmacology, Mendelian Randomization, and Molecular Docking.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111972},
doi = {10.1016/j.brainresbull.2026.111972},
pmid = {42259474},
issn = {1873-2747},
abstract = {PURPOSE: Zuo Gui Wan (ZGW), a traditional Chinese medicine formula, shows neuroprotective potential, but the mechanisms underlying its therapeutic effects on Alzheimer's disease (AD) remain unclear. This study aims to identify the active components, molecular targets, and biological pathways of ZGW in AD using an integrated systems pharmacology approach combining network analysis and causal inference.

METHODS: Active ZGW ingredients and targets were sourced from TCMSP and BATMAN-TCM. Summary-data-based Mendelian Randomization (SMR) and colocalization analyses integrated eQTL and AD GWAS data to identify gene-AD associations. Network pharmacology, GO/KEGG enrichment, PPI analysis, and molecular docking were conducted. Selected targets were examined by CCK-8 assay and Western blot in an Aβ25-35-induced SH-SY5Y neuronal injury model treated with ZGW-containing rat serum.

RESULTS: We identified 134 bioactive ZGW compounds targeting 391 AD-related genes. SMR prioritized six targets (ACE, SRC, STAT1, LEP, EGFR, and MAPK3) associated with neuroinflammatory and cardiovascular pathways. Molecular docking suggested strong interactions between key compounds and targets, notably berberine with SRC (-10.53kcal/mol) and compound 1 (PubChem CID: 137704703) with MAPK3 (-17.22kcal/mol). In the Aβ-induced neuronal model, ZGW-containing serum partially restored cell viability, reduced ERK1/2 and STAT1 phosphorylation, and increased ACE expression.

CONCLUSION: Integrated computational analyses prioritized six potential AD-related targets of ZGW, including ACE, SRC, STAT1, LEP, EGFR, and MAPK3. Preliminary cellular experiments further supported the involvement of MAPK3/ERK and STAT1 signaling, with increased ACE expression observed after ZGW treatment. These findings provide mechanistic insight into the potential therapeutic effects of ZGW in AD.},
}

@article {pmid42262554,
year = {2026},
author = {Paulzen, M},
title = {[Dextromethorphan-bupropion for the treatment of agitation in Alzheimer's disease].},
journal = {Der Nervenarzt},
volume = {},
number = {},
pages = {},
pmid = {42262554},
issn = {1433-0407},
}

@article {pmid42263197,
year = {2026},
author = {Miller, D and Lambert, S and Jordan, L and Butler, MJ and Sinvani, L and Perrin, A and Cheung, YK and Davidson, KW and Goodwin, AM},
title = {Multicomponent Behavior Change Technique Intervention for Caregivers of People With Alzheimer Disease and Related Dementias: Protocol for a Single-Arm, Personalized Behavioral Trial to Disrupt Sedentary Time.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e82857},
doi = {10.2196/82857},
pmid = {42263197},
issn = {1929-0748},
abstract = {BACKGROUND: Sedentary behavior is associated with negative health outcomes. High levels of sedentary behavior are common among Alzheimer disease and related dementias (ADRD) caregivers already at risk of other adverse health effects, yet few interventions target sedentary behavior within this population. There is a need for trials intended to reduce time spent sedentary, which may be achievable by increasing the frequency of disruptions to sedentary time. Remotely delivered behavior change techniques (BCTs) may be effective for disrupting sedentary behavior in this population through short bursts of walking, although it is unclear how BCTs promote this behavior and potentially act via the hypothesized mechanism of behavioral automaticity.

OBJECTIVE: The goal of the trial is to examine whether a significant proportion of ADRD caregivers (≥50%) receiving an SMS text message-delivered BCT intervention form a habit to engage in hourly walking 4 times per day, with the broader objective of disrupting sedentary time in this population.

METHODS: This trial is a 12-week, decentralized, single-arm, National Institutes of Health Stage II behavioral trial. The trial will deliver a personalized, multicomponent BCT intervention to disrupt time spent sedentary by encouraging forming a habit of hourly walking among caregivers of persons with ADRD via the key mechanism of behavior change behavioral automaticity. The intervention includes 4 daily SMS text message-delivered BCT components previously used in interventions to disrupt sedentary behavior-Goal setting, Action planning, Prompts/cues, and Self-monitoring. Formation of an hourly walking habit is the primary outcome and will be defined as walking an additional 250 steps or more per hour for the same 4 consecutive hours as set up in a personalized walking plan on 7 consecutive days. Secondary outcomes include evaluating associations between habit formation and behavioral automaticity, and between longitudinal behavioral automaticity and habitual hourly walking over time. Additionally, heterogeneity of treatment effects will be evaluated. Exploratory analyses will examine potential moderating variables that may influence the intervention effect. The trial uses digital enrollment strategies, SMS text message intervention delivery, passive data collection via Fitbit (Google) devices, and online survey assessments to collect data remotely.

RESULTS: This study was funded by the National Institute on Aging in June 2024. Recruitment and data collection began in March 2025. As of August 2025, 40% (n=40) of the planned sample has been enrolled. Data collection is expected to be complete by June 2026. Data analysis and publication of results are expected by Fall and Winter 2026, respectively.

CONCLUSIONS: Results will have the potential to advance knowledge about the effectiveness of BCTs to form a habit of hourly walking and may provide opportunities for future public health impact to promote physical activity in caregivers of those living with ADRD.},
}

@article {pmid42263407,
year = {2026},
author = {Wasilah, H and Gidafie, A and Amelia, VL and Chung, MH},
title = {Effectiveness of morning blue light therapy on sleep and daytime symptoms in adults with primary and comorbid insomnia: A systematic review and meta-analysis of randomized control trials.},
journal = {International journal of nursing studies},
volume = {182},
number = {},
pages = {105588},
doi = {10.1016/j.ijnurstu.2026.105588},
pmid = {42263407},
issn = {1873-491X},
abstract = {BACKGROUND: Insomnia is the most prevalent sleep complaint, occurring as a primary or comorbid condition, increasing the public healthcare burden. Prior reviews examined the efficacy of blue light therapy in improving sleep among patients with a traumatic brain injury and young adults and reported conflicting results. A comprehensive evaluation of blue light therapy on sleep quality, sleep parameters, daytime sleepiness, and fatigue across adults with primary insomnia and insomnia with comorbid condition has not been fully established.

METHODS: This study was conducted in accordance with the PRISMA 2020 statement. We searched EBSCO, Embase, OVID, PubMed, Scopus, Trials.Gov, Web of Science, and PROSPERO for eligible studies published between the date of database inception and 16 April 2025. The Cochrane risk of bias tool was used to assess study quality. A random-effects model was employed to calculate the pooled effects. Subgroup analyses were performed to identify potential moderators.

RESULTS: We included 14 articles involving 444 insomniacs with a neurological disease (mild traumatic brain injury, Alzheimer's disease, or dementia) or medical disease (cancer, diabetes, or fibromyalgia) or with no comorbidity. Studies were conducted in several Asian and European countries, as well as the United States and Australia. The results indicated that blue light therapy improved subjective sleep quality [mean difference (MD) = -1.895], excessive daytime sleepiness (MD = -0.970), and several objective sleep parameters [sleep onset latency (Hedges' g = -0.545), waking after sleep onset (Hedges' g = -0.563), sleep efficiency (Hedges' g = 0.429), sleep fragmentation (Hedges' g = -1.228), and number of awakenings (Hedges' g = -0.614)]. Blue light therapy did not improve the fragmentation index, time in bed, or total sleep time and did not significantly reduce fatigue. The type of device, intervention duration, and light intensity moderated sleep quality. The intervention duration and frequency moderated sleep efficiency.

CONCLUSIONS: In adults with insomnia with diverse clinical backgrounds, blue light therapy may provide modest improvement in sleep quality and certain sleep parameters related to advancement and continuity of sleep (sleep fragmentation, sleep onset latency, waking after sleep onset, number of awakenings, and sleep efficiency), and may alleviate excessive daytime sleepiness. These findings suggest that blue light therapy may be considered potential non-pharmacological treatment for insomnia that can be implemented by healthcare providers in home or clinical settings. However, these findings should be interpreted with caution. Further studies are needed to confirm these findings.

REGISTRATION: The review was registered with PROSPERO (CRD420251027417).},
}

@article {pmid42263916,
year = {2026},
author = {Sandrine, MNY and Blondelle, NM and Franklin, ZG and Emmanuel, OP and Ronald, BAG and Cynthia, BYP and Ogunlakin, AD and Claude, BD and Samir, C and Désiré, DDP},
title = {Neuroprotective Effects of Aqueous Extract of Pterocarpus mildbraedii Harms. on Some Biochemical Markers in Alzheimer's Disease Using an AlCl3-induced Rat Model: Integrated ADMET, Network Pharmacology, Molecular Docking, and In Vivo Experimental Validation.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121962},
doi = {10.1016/j.jep.2026.121962},
pmid = {42263916},
issn = {1872-7573},
abstract = {ETHNOPHARMACOLOGY RELEVANCE: Neurodegenerative diseases such as Alzheimer's often lack effective conventional treatments. Phytotherapy is emerging as a promising approach to managing these conditions. Pterocarpus mildbraedii Harms. (P. mildbraedii), a plant from the Fabaceae family, which is traditionally used to treat convulsions, headaches, and fever. This study is designed to evaluate the neuroprotective effects of the aqueous extract of Pterocarpus mildbraedii Harms. on biochemical markers of Alzheimer's disease in an AlCl3-induced rat model using integrated ADMET, network pharmacology, molecular docking, and in vivo validation.

METHODS: We employed network pharmacology and in silico molecular docking to identify bioactive compounds and assess their binding affinities to key proteins: VCP, MAPK1, MMP9, PTGS1, IL6, and AR. The in vivo experiment lasted 56 days, with 30 animals divided into 5 groups (n = 6 per group). They received daily oral doses of distilled water (10 mL/kg), AlCl3 (75 mg/kg), Donepezil (5 mg/kg) after AlCl3, or P. mildbraedii bark water extract at 150 mg/kg (PM 150) and 300 mg/kg (PM 300) following AlCl3. On Days 23 and 51, all animals underwent open-field and Morris water maze tests. On Day 57, animals were sacrificed, and calcium levels, oxidative markers, and neurotransmitter levels were measured in homogenates from the amygdala, hippocampus, and prefrontal cortex. Histopathological analysis of the hippocampus and amygdala was also conducted.

RESULTS: In silico studies showed that the plant compounds pterocarpan and liquiritigenin bound strongly to VCP, MAPK1, and MMP9, with binding energies lower than those of reference inhibitors, indicating greater stability. In vivo, AlCl3 caused anxiety, locomotor issues (p< 0. 001), memory impairment (p< 0. 001), and disrupted GABA, ACh metabolism, and AChE activity. It also reduced antioxidant levels (p< 0.001), increased pro-oxidants (p< 0.001), and elevated calcium and Tau protein levels compared to the normal control. Treatment with Pterocarpus mildbraedii extract mitigated these effects, reducing anxiety and enhancing memory, locomotion, ACh, and GABA levels, as well as AChE activity. The extract notably decreased Tau protein and MDA concentrations by 80. 57% in the amygdala, 63. 80.57% in the prefrontal cortex, and 63.73. 50% in the hippocampus, and nitrites. It also significantly increased protein levels, GSH (by 6.95-fold in the amygdala, 80.48% in the prefrontal cortex, and 85.75% in the hippocampus), SOD, and catalase activities across brain regions compared with the AlCl3-treated group.

CONCLUSION: These findings suggest that Pterocarpus mildbraedii extract, with its antioxidant, anti-amnesic, and anxiolytic properties, offers neuroprotection and may have neuroprotective effects in Alzheimer 's-like neurotoxicity.},
}

@article {pmid42264545,
year = {2026},
author = {Vishwakarma, H and Chauhan, A and Kaur, L and Awasthi, A},
title = {Nanotechnology-enabled targeting strategies for neurodegenerative disorders: role of functionalized nanoparticles.},
journal = {The Journal of pharmacy and pharmacology},
volume = {78},
number = {6},
pages = {},
doi = {10.1093/jpp/rgag060},
pmid = {42264545},
issn = {2042-7158},
abstract = {BACKGROUND: Neurodegenerative disorders comprise a diverse group of progressive neurological diseases characterized by the gradual loss of neuronal structure and function. Conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis arise from multifactorial mechanisms involving genetic susceptibility, environmental factors, and age-related cellular decline.

PATHOPHYSIOLOGY: Key pathogenic processes include oxidative stress, mitochondrial dysfunction, protein misfolding and aggregation, impaired axonal transport, Golgi fragmentation, and chronic neuroinflammation, all of which disrupt neuronal homeostasis and synaptic communication, ultimately leading to neuronal death. Hormonal imbalances further exacerbate these effects by promoting oxidative damage, inflammation, and metabolic dysfunction.

CHALLENGES IN THERAPY: Despite advances in understanding disease mechanisms, effective drug delivery remains challenging due to the restrictive nature of the blood-brain barrier.

Recent developments highlight the potential of nanoparticle-based drug delivery systems to overcome these limitations. Functionalized nanoparticles enhance blood-brain barrier penetration, improve targeting specificity, and enable controlled drug release. These systems can deliver neuroprotective agents, antioxidants, peptides, and gene therapies directly to affected brain regions. Thus, integrating disease pathophysiology with nanotechnology-based strategies offers a promising approach for improving therapeutic outcomes and advancing precision treatment in neurodegenerative disorders.},
}

@article {pmid42265098,
year = {2026},
author = {Belmont-Rausch, DM and Ludwig, MQ and Bentsen, MA and Hansen, SN and Secher, A and Holst, D and Moreno, J and Das, V and Egerod, KL and Bjerregaard, AM and Niss, K and Bau, S and Pyke, C and Dalgaard, K and Merkestein, M and Wichern, F and Hansen, CT and Polex-Wolf, J and Knudsen, LB and Pers, TH},
title = {Semaglutide attenuates neuroinflammation in male mice.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-74038-4},
pmid = {42265098},
issn = {2041-1723},
support = {NNF18CC0034900//Novo Nordisk Fonden (Novo Nordisk Foundation)/ ; R190-2014-3904//Lundbeckfonden (Lundbeck Foundation)/ ; 8045-00091B//Det Frie Forskningsråd (Danish Council for Independent Research)/ ; R01 DK124238/DK/NIDDK NIH HHS/United States ; },
abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promise in preclinical models of neurodegeneration, with emerging evidence suggesting these effects may be driven by modulation of neuroinflammation. However, the cellular mechanisms underlying GLP-1RA effects on neuroinflammation remain poorly understood. Here we show, using a mouse model of lipopolysaccharide-induced neuroinflammation, how semaglutide coordinates cellular responses to resolve neuroinflammation. We find that semaglutide in male mice prevents brain infiltration of neutrophils, excessive cytokine release, and suppresses neuroinflammation-associated transcriptional signatures specifically in microglia, endothelial cells, and a subset of pericytes. Mechanistically, we identify a subset of Glp1r-expressing neurons in the dorsal vagal complex that, upon semaglutide treatment, regulate genes involved in anti-inflammatory signaling. Semaglutide-modulated pathways overlap with inflammatory signatures found in human neurodegenerative diseases, including Alzheimer's disease, suggesting broad relevance for conditions involving neuroinflammation. Together, these findings reveal how GLP-1R signaling in male mice orchestrates resolution of neuroinflammation through coordinated multi-cellular programs.},
}

@article {pmid42266233,
year = {2026},
author = {Chen, Z and Zhang, Y and Zhu, X and Wu, H and Yu, T and Liu, Z},
title = {Comparative efficacy of exercise interventions on depressive symptoms and related outcomes in patients with Alzheimer's disease, cognitive impairment, and Parkinson's disease: a systematic review and network meta-analysis.},
journal = {Frontiers in physiology},
volume = {17},
number = {},
pages = {1825740},
pmid = {42266233},
issn = {1664-042X},
abstract = {BACKGROUND: Patients with Alzheimer's disease, cognitive impairment, and Parkinson's disease often experience depressive symptoms, which negatively impact quality of life and disease management. Exercise is an important non-pharmacological treatment in these populations; however, the relative efficacy of different exercise modalities remains unclear. This study used a systematic review and network meta-analysis to compare the effects of various exercise interventions on depressive symptoms and related outcomes.

METHODS: We systematically searched Chinese and English databases for randomized controlled trials evaluating exercise interventions in patients with Alzheimer's disease, cognitive impairment (including mild cognitive impairment and dementia), and Parkinson's disease. The primary outcome was depressive symptoms, assessed by using Geriatric Depression Scale (GDS) and Beck Depression Inventory (BDI); the secondary outcomes were cognitive function and motor function, assessed by using Mini-Mental State Examination (MMSE) and Unified Parkinson's Disease Rating Scale Part III (UPDRS III), respectively. Network meta-analysis was performed using Stata 16.0, and supplementary pairwise meta-analyses by disease type were conducted for the primary outcomes. RevMan 5.4 was used to assess the risk of bias, and the CINeMA framework was used to evaluate the credibility of the evidence.

RESULTS: A total of 23 randomized controlled trials involving 1,596 subjects were included. For the primary outcomes, no exercise modality showed an overall statistically significant advantage over the control group in improving depressive symptoms. For the secondary outcome, cognitive exercise significantly improved the MMSE scores compared with daily activities (MD = 3.50, 95% CI [2.29, 4.71]). For UPDRS III, no significant overall difference was observed between exercise interventions and the control group.

CONCLUSION: The available evidence does not provide stable or modestly consistent support for a clear overall benefit of different exercise interventions on depressive symptoms in patients with Alzheimer's disease, cognitive impairment, and Parkinson's disease. Cognitive exercise may help improve cognitive function, whereas the potential benefits of multicomponent exercise for motor function in Parkinson's disease should be interpreted with caution. In the future, large randomized controlled trials with clearer stratification, specific protocols, and standardized exercise prescriptions are needed to further define the optimal populations and intervention effects of different exercise modalities.

https://www.crd.york.ac.uk/prospero/, identifier CRD420261280926.},
}

@article {pmid42255958,
year = {2026},
author = {Trudel, L and Therriault, J and Macedo, AC and Meeker, KL and Braskie, MN and Toga, AW and Gauthier, S and Vitali, P and Schindler, SE and O'Bryant, SE and Rosa-Neto, P},
title = {Eligibility for anti-amyloid treatment in a multiethnic community-based study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70314},
pmid = {42255958},
issn = {2352-8729},
abstract = {INTRODUCTION: The approval of anti-amyloid monoclonal antibodies (mAbs), including lecanemab and donanemab, represents a significant advance in disease-modifying therapies (DMTs) for early Alzheimer's disease (AD). While appropriate use recommendations (AURs) have been established to guide clinical decision-making, the proportion of individuals with cognitive impairment in real-world, multiethnic populations meeting eligibility criteria remains unknown, as do potential differences in treatment-related risks across ethnic groups.

METHODS: We included 513 cognitively impaired individuals from the Health and Aging Brain Study-Health Disparities study, a multiethnic community-based cohort. Eligibility for lecanemab and donanemab was determined using published AUR criteria. Counts of amyloid-related imaging abnormalities were estimated based on apolipoprotein E (APOE) ε4 genotype and ethnicity using published incidence rates.

RESULTS: Only 15% of participants met eligibility criteria for lecanemab or donanemab. Black individuals had a numerically higher estimated ARIA burden, though differences were not statistically significant.

DISCUSSION: Few individuals in this community-based, multiethnic cohort met eligibility for anti-amyloid therapy, highlighting limited real-world applicability of current AURs.

HIGHLIGHTS: Only 15% of community-based individuals with MCI or dementia met eligibility criteria for lecanemab and donanemab.Black participants had numerically higher estimated ARIA cases, though not statistically significant.Current AUR criteria have limited real-world applicability across multiethnic populations.Broader inclusion criteria and real-world safety data are needed to ensure equitable, safe implementation.},
}

@article {pmid42255964,
year = {2026},
author = {Rosenbloom, M and Adams, C and Allen, B and Berry, B and Camargo, C and Cooper, G and Giles, S and Leahy, C and Sabbagh, M and Sadowski, M and Schreiber, C and Schulz, PE and Soria, J and Weisman, D and Frech, F and Jones, DR},
title = {Real-world use of lecanemab: patient pathway findings from a US multicenter study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70376},
pmid = {42255964},
issn = {2352-8729},
abstract = {INTRODUCTION: To ensure Alzheimer's disease-modifying treatments can be initiated in diverse populations, efficient pathways to obtain timely diagnoses are required.

METHODS: This interim sub-analysis of a multicenter US study included cross-sectional surveys and interviews with neurologists at 12 diverse sites to assess real-world lecanemab use.

RESULTS: At survey completion, ∼1342 patients had received lecanemab. Most referrals originated from primary care. Amyloid pathology was confirmed primarily by positron emission tomography (58%) or cerebrospinal fluid (35%), with blood-based biomarkers (BBMs) increasingly used to reduce diagnostic delays. All sites performed apolipoprotein E4 (APOE ε4) testing to inform risk/benefit decisions. Infusions usually started within 6 months of diagnosis. Delayed/incomplete referrals were identified as the most significant barrier in the current patient pathway.

DISCUSSION: These findings demonstrate the feasibility of lecanemab integration in diverse clinical settings and highlight the importance of primary care physician engagement, optimization of referral pathways, and expanding BBM use in improving timely diagnosis, equitable access, and early treatment initiation.},
}

@article {pmid42250049,
year = {2026},
author = {Khan, Y and Rekha, A and Ballal, S and Maharana, L and Maqbool, M and Goyal, K and Mishra, R and Uniyal, P and Alam, P and Aljarba, TM and Gupta, G and Hussain, MS},
title = {Omics-driven strategies for identifying biomarkers in Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42250049},
issn = {1573-7365},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options, mainly due to late diagnosis and partial understanding of its molecular aspects. Traditional biomarker discovery approaches have significantly contributed to AD diagnostics but suffer from limitations. The advent of omics technologies (genomics, epigenomics, transcriptomics, proteomics, and metabolomics) has revolutionized the search for novel biomarkers by enabling comprehensive molecular profiling. Genomic studies have identified risk-associated variants such as APOE4, while epigenomic alterations, including DNA methylation alterations, offer insight into gene regulation in AD. Transcriptomic analyses, particularly single-cell and spatial transcriptomics, have uncovered molecular pathways linked to neuroinflammation and synaptic dysfunction. Proteomic advancements, including mass spectrometry and extracellular vesicle profiling, have identified potential blood- and CSF-based biomarkers for early-stage detection. Metabolomic and lipidomic studies indicate that cerebral glucose hypometabolism, insulin resistance, mitochondrial damage, redox imbalance, and disrupted lipid homeostasis are centra contributors to AD pathogenesis rather than secondary considerations of the disease. These metabolic dysfunctions may precede overt neurodegeneration and influence amyloid processing, tau phosphorylation, neuroinflammatory activation, and synaptic loss, thereby generating clinically informative biomarker signatures in blood and cerebrospinal fluid. Within this metabolism-centered paradigm, integrative multi-omics approaches are particularly valuable because they not only enhance biomarker specificity, but also connect molecular signatures with bioenergetic and immune-mediated mechanisms of disease. Accordingly, integrative multi-omics approaches improve biomarker specificity and predictive power, thereby supporting the development of precision medicine and targeted therapeutic interventions. Nevertheless, important challenges remain, including data integration, reproducibility, and clinical translation.},
}

@article {pmid42250112,
year = {2026},
author = {Carrasco, M and Guzman, L and Barroso, E and Olloquequi, J and Cano, A and Ureña, J and Verdaguer, E and Prohens, R and Fortuna, A and Auladell, C and Ettcheto, M and Camins, A},
title = {Licochalcone a enhances cognitive resilience in APP/PS1 Mice by modulating glucose metabolism, Aβ burden, and neuroinflammation.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42250112},
issn = {2509-2723},
support = {PID2021-123462OB-I00//Ministerio de Ciencia e Innovación/ ; PID2023-146632OB-I00//Ministerio de Ciencia e Innovación/ ; PID2021-122473OA-I00//Ministerio de Ciencia e Innovación/ ; 2021 SGR 00288//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; Grant CB06/05/2004//CIBERNED/ ; CEX2021-001159-M//Institut de neurociencies/ ; EBLE-9051//Serra Hunter Contract/ ; UB-LE-9115//Serra Hunter Contract/ ; UB-LE-9035//Serra Hunter contract/ ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder. Current therapeutic approaches targeting a single pathway have shown limited efficacy, highlighting the need for multi-target interventions. Licochalcone A (LCA), a chalcone of licorice root, has demonstrated anti-inflammatory and antidiabetic properties. However, its potential neuroprotective mechanisms in AD remain unclear. The present study aims to elucidate the beneficial effect of LCA against cognitive decline in an AD mouse model. For this purpose, five-month-old APPswe/PS1dE9 (APP/PS1) mice received intraperitoneal LCA (15 mg·kg[-1]·day[-1]) treatment for 4 weeks. Afterwards, cognitive function was assessed using Morris water maze (MWM) and Novel object recognition test (NORT). Metabolism was evaluated through glucose and insulin tolerance tests. Biochemical markers of synapses, neurogenesis, metabolism, Amyloid-β (Aβ) burden and neuroinflammation were analyzed using immunohistochemistry, Thioflavin-S staining, Golgi staining, Western blot, ELISA and RT-PCR. The results demonstrated that LCA significantly improved long-term memory in APP/PS1 mice, through MWM and NORT, accompanied by an increased dendritic spine density, upregulated PSD95 and spinophilin levels, and enhanced Ki67-positive cells in the hippocampus. Moreover, LCA treatment ameliorated glucose tolerance and initial insulin response while increasing Insr expression and GLUT1 protein levels. Furthermore, LCA-treated APP/PS1 mice showed reduced plaque burden and Aβ42 levels. Alongside, LCA demonstrated its anti-inflammatory effect by reducing glial reactivity, and Trem2 expression. In conclusion, the present study demonstrates the multiple therapeutic effects of LCA in APP/PS1 mice by simultaneously modulating glucose metabolism, reducing Aβ accumulation and attenuating neuroinflammation, ultimately enhancing cognitive resilience. These findings establish LCA as a promising multi-target compound for AD treatment.},
}

@article {pmid42250142,
year = {2026},
author = {Jalaiei, A and Kiani Darabi, AH and Sakkaki, E and Rezazadeh, M and Ghafouri-Fard, S},
title = {Molecular interplay between Non-coding RNAs and BDNF in Neurodegenerative Disorders: a systematic review.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42250142},
issn = {1573-4978},
abstract = {Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays essential roles in nervous system development, neuronal maintenance, and neurogenesis. Aberrant BDNF concentrations, observed both peripherally and within the central nervous system (CNS), have been consistently implicated in the pathogenesis of a spectrum of neurodegenerative disorders (NDDs), including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and Multiple sclerosis. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), regulate gene expression and are critical factors in cellular processes relevant to neurodegenerative disease pathobiology. Consequently, ncRNAs are posited as promising biomarkers and potential therapeutic modalities for CNS-related pathologies. However, robust empirical evidence substantiating ncRNA-mediated, post-transcriptional regulation of BDNF expression in the context of neurodegeneration remains relatively scarce. The objective of this systematic review is to provide a critical synthesis of the current literature on the diagnostic and prognostic utility of ncRNAs that modulate BDNF expression, specifically within the scope of neurodegenerative disorders. Furthermore, we will explore innovative therapeutic strategies centered on targeting BDNF-associated miRNAs for the treatment of these disorders.},
}

@article {pmid42250492,
year = {2026},
author = {Ahn, S and Salas, J and Cho, J and Scherrer, JF},
title = {Combined effect of anxiety disorder and insomnia on the risk of incident ADRD diagnosis.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100621},
doi = {10.1016/j.tjpad.2026.100621},
pmid = {42250492},
issn = {2426-0266},
abstract = {BACKGROUND: Anxiety disorders and insomnia are common modifiable conditions in older adults, but their independent and combined effects on the risk of incident Alzheimer's disease and related dementias (ADRD) remain unclear.

OBJECTIVES: To estimate the independent and combined associations of anxiety disorders and insomnia with the risk of incident ADRD.

DESIGN: Retrospective cohort study using an intention-to-treat approach with a 10-year follow-up period (2014-2023).

SETTING: De-identified electronic health record (EHR) data from 70 participating healthcare organizations within the TriNetX Research Network.

PARTICIPANTS: Adults aged ≥50 years without prior dementia who had regular ambulatory care during a three-year baseline period (n = 1,868,790).

MEASUREMENTS: Anxiety and insomnia were identified using ICD-based algorithms and categorized into four exposure groups: neither condition, anxiety only, insomnia only, and both. Incident ADRD was defined by two or more diagnostic codes within 12 months. Entropy balancing controlled for confounding, and weighted Cox proportional hazards models estimated hazard ratios (HRs).

RESULTS: At baseline, 4.1% had anxiety only, 3.8% had insomnia only, and 1.1% had both. Over follow-up, 2.3% developed ADRD. In weighted models, insomnia alone (HR: 1.12; 95% CI: 1.06-1.19), anxiety alone (HR: 1.49; 95% CI: 1.39-1.60), and co-occurring anxiety and insomnia (HR: 1.31; 95% CI: 1.06-1.62) were each associated with higher ADRD risk compared with neither condition. No significant effect modification by age, sex, or race was observed.

CONCLUSIONS: Anxiety and insomnia independently increase ADRD risk, though insomnia's contribution is very modest compared to the primary association demonstrated by anxiety. Co-occurrence does not confer additional risk beyond anxiety alone. Clinically, routine screening and treatment of anxiety and sleep disturbances represent actionable, broadly applicable strategies for ADRD prevention and healthy cognitive aging.},
}

@article {pmid42251444,
year = {2026},
author = {Contreras-Marciales, A and Mezquite-Garcia, D and Verdina, LA and Elnahrawy, A and Wolf, T and Guergues, J and Parikh, P and Hunter, ER and Hernandez Acosta, D and Stevens, SM and Hill, SE and Blair, LJ},
title = {FKBP51 inhibition by SAFit2 modulates tau pathology and cognitive deficits in PS19 mice.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02107-3},
pmid = {42251444},
issn = {1758-9193},
support = {R01 NS073899/NS/NINDS NIH HHS/United States ; R01 NS073899/AG/NIA NIH HHS/United States ; I01 BX004626/BX/BLRD VA/United States ; AARG-22-974562/ALZ/Alzheimer's Association/United States ; },
abstract = {The accumulation of pathogenic tau protein is linked to cognitive decline and neuronal loss in Alzheimer's disease (AD), with tau oligomers identified as particularly neurotoxic. The 51 kDa FK506-binding protein (FKBP51) stabilizes these toxic tau oligomers and has been identified as a risk factor for several neurodegenerative diseases. FKBP51 levels increase with age and are especially high in AD brains, suggesting its involvement in disease progression. The development of the selective FKBP51 inhibitor, SAFit2, which can cross the blood-brain barrier, has shown promise in reducing stress hormones, improving stress responses, and mitigating protein-related pathologies in other neurodegenerative models. However, the effects of SAFit2 on tauopathies, such as those seen in AD, have not yet been investigated. Here, the effects of the FKBP51-selective inhibitor, SAFit2, were evaluated in PS19 tau transgenic mice. Mice received a 28-day regimen of SAFit2, followed by comprehensive behavioral, neuropathological, and proteomic analyses. SAFit2 demonstrated effective brain penetrance, with sex-dependent pharmacokinetics. Treatment slowed cognitive decline and depressive-like behavior, with pronounced benefits in male PS19 mice, including improved spatial memory and reduced tau oligomer burden. In females, SAFit2 promoted clearance of AT8-positive tau multimers with some benefit to recognition memory. Proteomic profiling revealed distinct molecular signatures underlying these sex-specific responses: males exhibited upregulation of RNA processing and ribosomal proteins, while females showed restoration of calcium signaling and synaptic drivers. Notably, behavioral recovery occurred independently of widespread neuroinflammation reversal. These findings provide the first in vivo evidence that FKBP51 inhibition by SAFit2 induces sex-specific remodeling of the brain proteome. This study also provides further evidence for the therapeutic benefits of targeting FKBP51 for tauopathies.},
}

@article {pmid42251712,
year = {2026},
author = {Reyzov, M and Valcheva-Kuzmanova, S},
title = {Neuropsychopharmacological effects of Aronia melanocarpa: A narrative review.},
journal = {Psychiatria Danubina},
volume = {38},
number = {1},
pages = {12-22},
doi = {10.24869/psyd.2026.12},
pmid = {42251712},
issn = {0353-5053},
abstract = {BACKGROUND: This narrative review examines the neuropsychopharmacological effects of Aronia melanocarpa (black chokeberry), focusing on its potential in the prevention and treatment of neuropsychiatric disorders such as anxiety, depression, and cognitive decline.

SUBJECTS AND METHODS: A comprehensive literature search across Web of Science, Scopus, and Google Scholar identified 29 original studies, based on in vitro, animal, and human research.

RESULTS: Findings demonstrated that Aronia melanocarpa, rich in polyphenols like anthocyanins and proanthocyanidins, exerts cognitive-enhancing, anxiolytic-like, and antidepressant-like effects. These outcomes are mediated by mechanisms involving antioxidant activity, modulation of neurotransmitter systems, inhibition of monoamine oxidases, reduction of neuroinflammation, modulation of gut microbiota, and upregulation of brain-derived neurotrophic factor (BDNF). Animal models of Alzheimer's disease and stress-induced disorders, along with human clinical trials, corroborated these effects.

CONCLUSIONS: The review underscores the therapeutic promise of Aronia melanocarpa nutraceuticals in neuropsychiatric health and highlights the need for further clinical validation.},
}

@article {pmid42252274,
year = {2026},
author = {Yu, Z and Wang, Y and Li, Y and Shen, F and Wang, Y},
title = {[Research progress on vascular endothelial growth factor C in meningeal lymphatic vessel-mediated clearance of amyloid β-protein].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {},
number = {},
pages = {1-8},
doi = {10.3724/zdxbyxb-2025-0549},
pmid = {42252274},
issn = {1008-9292},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the abnormal deposition of amyloid β-protein (Aβ) as a core pathological feature. Meningeal lymphatic vessels are crucial for Aβ clearance, and their dysfunction accelerates AD progression. Vascular endothelial growth factor C (VEGF-C), through activation of vascular endothelial growth factor receptor 3 and downstream pathways, synergistically promotes lymphangiogenesis, enhances lymphatic permeability, and regulates lymphatic fluid flow, thereby improving Aβ clearance efficiency. Genetic factors and aging-related declines in VEGF-C further impair meningeal lymphatic function, creating a vicious cycle. Although VEGF-C intervention has shown cognitive benefits in AD models, clinical translation faces challenges including non-specific activation of signaling pathways and interindividual variability. Future research should focus on precise regulation of VEGF-C and development of individualized AD therapeutic strategies targeting meningeal lymphatic vessels. This review summarizes the molecular mechanisms, influencing factors, and intervention strategies of VEGF-C in regulating meningeal lymphatic vessel function to promote Aβ clearance, aiming to provide insights for AD prevention and treatment.},
}

@article {pmid42252335,
year = {2026},
author = {Behl, T and Jayabalan, K and Ballal, S and Sahoo, S and Jayasingh Chellammal, HS and Gulati, M and Anand, K and Jha, SK and Gasmi, A},
title = {A Age Related Vascular Senescence: Mystery of Blood-brain Barrier Dysfunction in Neurodegeneration.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42252335},
issn = {1559-1182},
mesh = {Humans ; *Blood-Brain Barrier/pathology/physiopathology/metabolism ; *Aging/pathology ; Animals ; *Neurodegenerative Diseases/pathology/physiopathology ; },
abstract = {The pathophysiology of neurodegenerative illnesses is increasingly understood to be influenced by vascular aging, with blood-brain barrier (BBB) disruption emerging as a crucial mechanistic connection. Comprising endothelial cells, pericytes, astrocytes, and microglia, the BBB is a complex neurovascular unit (NVU) that strictly regulates molecular trafficking and shields neural tissue from circulating toxins and immune cells, therefore maintaining central nervous system homeostasis. The integrity of the BBB is compromised as people age due to structural and functional changes in the cerebrovasculature, such as endothelial senescence, pericyte loss, mitochondrial dysfunction, and persistent low-grade inflammation. These alterations speed up neuronal damage and encourage the development of classical proteinopathies like tau aggregation and amyloid-β by making it easier for neurotoxic proteins, immunological mediators, and metabolic waste to enter the brain parenchyma. BBB disruption is both an early occurrence and a factor in the development of neurodegenerative diseases including Alzheimer's disease, cerebral amyloid angiopathy, and vascular dementia. It exacerbates neuroinflammation, hinders clearance processes, and contributes to cognitive decline. Recent developments in single-cell omics, fluid biomarkers, and molecular imaging have made it possible to identify and characterize BBB failure in preclinical and clinical contexts, creating new opportunities for early diagnosis and treatment. Restoring BBB function and addressing vascular aging are two viable approaches to alter the course of neurodegenerative illnesses and enhance their prognoses. The processes, effects, and translational potential of vascular aging and BBB degradation in neurodegeneration are summarized in this review, which also identifies new treatment targets and research objectives for the future.},
}

Humans
*Blood-Brain Barrier/pathology/physiopathology/metabolism
*Aging/pathology
Animals
*Neurodegenerative Diseases/pathology/physiopathology

@article {pmid42252551,
year = {2026},
author = {Chiatto, LM and Buccarello, L and Carota, G and Calabrò, RS and Rifici, C and Esposito, E and Ardizzone, A and Caruso, G},
title = {The Use of Statins in Parkinson's and Alzheimer's Disease: A 2021-2025 State-of-the-Art Review of Clinical and Preclinical Evidence.},
journal = {Pharmacology research & perspectives},
volume = {14},
number = {3},
pages = {e70280},
doi = {10.1002/prp2.70280},
pmid = {42252551},
issn = {2052-1707},
abstract = {Statins, widely prescribed for cardiovascular prevention, have emerged as potential disease-modifying agents in neurodegenerative disorders due to their pleiotropic effects on cholesterol metabolism, neuroinflammation, oxidative stress, and protein aggregation. Over the past decade, growing interest has focused on the potential repurposing of statins for Parkinson's disease (PD) and Alzheimer's disease (AD); however, clinical evidence remains heterogeneous and, in some cases, contradictory. This state-of-the-art review synthesizes clinical and preclinical studies published between 2021 and 2025 to critically evaluate the therapeutic potential and limitations of statins in PD and AD. Recent observational studies and large-scale cohort analyses suggest that long-term statin use may be associated with a reduced risk of incident PD and AD, as well as slower cognitive decline in selected patients' subgroups. However, these associations appear to depend on factors such as statin lipophilicity, treatment duration, and genetic background. Preclinical models provide mechanistic support, showing that statins can attenuate neuroinflammation, modulate microglial activation, reduce α-synuclein aggregation in PD models, and interfere with amyloid-β production and tau phosphorylation in AD models. Nevertheless, randomized controlled trials remain limited in number and often underpowered, and some reports indicate neutral or even adverse neurological outcomes, underscoring the complexity of cholesterol-dependent and cholesterol-independent mechanisms in the central nervous system (CNS). Collectively, the evidence from 2021 to 2025 highlights both the therapeutic promise and the unresolved challenges of statin repurposing in neurodegenerative diseases. Future research should prioritize well-designed clinical trials and biomarker-driven patient stratification to determine whether statins can be effectively leveraged as adjunctive disease-modifying therapies in PD and AD.},
}

@article {pmid42252587,
year = {2026},
author = {Jin, H},
title = {PET Molecular Probes for Neuroinflammation in Neurodegenerative Diseases: Progress and Prospects.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00338},
pmid = {42252587},
issn = {1948-7193},
abstract = {Neuroinflammation is a central pathological process underlying neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis. Positron emission tomography (PET) molecular probes now enable the noninvasive, quantitative visualization of neuroinflammatory processes in the living brain. This review surveys recent advances in PET probes targeting microglial activation markers─including the 18 kDa translocator protein (TSPO), the purinergic P2X7 receptor (P2X7R), colony-stimulating factor 1 receptor (CSF1R), and sphingosine-1-phosphate receptor 1 (S1PR1)─as well as astrocyte reactivity markers such as monoamine oxidase B (MAO-B) and imidazoline-2 binding sites (I2BS). I discuss the evolution from first-generation TSPO ligands to polymorphism-insensitive third-generation tracers, highlight emerging targets beyond TSPO, and evaluate the translational value of these probes for early diagnosis, disease staging, treatment monitoring, and drug development. Current challenges-including limited cellular specificity, genetic polymorphism effects, quantification difficulties, and clinical accessibility barriers─are analyzed alongside promising solutions. Integrating neuroinflammation PET into multimodal biomarker frameworks will be essential for advancing precision medicine in neurodegenerative diseases.},
}

@article {pmid42253201,
year = {2026},
author = {Tarkowska, A and Furmaga-Jabłońska, W and Pluta, R},
title = {Long-Term Consequences of Perinatal Asphyxia in the Development of Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050432278251204130006},
pmid = {42253201},
issn = {1875-5828},
abstract = {Despite remarkable progress in medicine, perinatal asphyxia (PA) remains a significant clinical problem, and concerns regarding its long-term complications are increasingly being raised. Emerging evidence indicates that similar pathological pathways are activated following PA and during neurodegeneration in Alzheimer's disease (AD). These similarities involve various mechanisms, including alterations in AD-related proteins and their gene expression. Disturbances in neurotransmitter function can lead to excitotoxicity and cell death via necrosis and delayed apoptosis. Additionally, as observed in AD, dysregulation of autophagic processes has been reported. Pathological changes initiated by hypoxia in the newborn may trigger chronic neuroinflammation that persists long-term. Similarly, neuroinflammation plays a critical role in the pathogenesis of AD. Other common mechanisms include oxidative stress and mitochondrial dysfunction. Estrogens appear to have a protective effect in both PA and AD; however, ovaries exposed to PA may exhibit a reduced ovarian reserve, potentially diminishing neuroprotection later in life. Epigenetic modifications have also been proposed as a link between PA and AD. This review focuses on the changes that occur in the neonatal brain following PA, with particular emphasis on long-term consequences. We highlight common pathogenetic and causal pathways that may connect PA to the development of AD. Furthermore, we summarize key studies from the past 25 years addressing these topics and briefly discuss current research directions in the treatment of experimental and clinical PA.},
}

@article {pmid42253387,
year = {2025},
author = {Persaud, V and Wertheimer, AI},
title = {Assessing the Equitable Use of Formulary Drug Tier Systems: Consequences for Geriatric Patient Population Access and Accessible Medication.},
journal = {Innovations in pharmacy},
volume = {16},
number = {2},
pages = {},
pmid = {42253387},
issn = {2155-0417},
abstract = {Background: This study examines the implications of formulary drug tier systems on the accessibility and affordability of medications for the elderly/geriatric population within the New York metropolitan area. By systematically reviewing the Medicare insurance formularies and evaluating the most prescribed medicines with reported beneficial outcomes for ailments frequently experienced by the geriatric population, this research identifies disparities in drug tier placements and the cost of dispensing that may affect patient outcomes. The focus is on five prevalent conditions: Alzheimer's dementia, Chronic Obstructive Pulmonary Disease, Rheumatoid Arthritis, Ischemic Heart Disease, and Diabetes Mellitus Type 2 (T2DM). The findings aim to highlight the need for more equitable healthcare policies that consider the financial and medical needs of the elderly population. Methods: This study reviewed the formulary tier systems used by Medicare, the primary insurance provider for the elderly in New York City. The research focused on medications prescribed for Alzheimer's disease, COPD, rheumatoid arthritis, ischemic heart disease, and diabetes. Data on tier placements were extracted from Medicare Part D formularies, with a detailed examination of the criteria for tier assignment. The study identified the three most prescribed medications for each condition, using data from relevant health organizations and literature. An economic analysis was conducted to compare the costs associated with these medications, assessing the financial burden on patients. Results: The study revealed a prevalence of chronic conditions among New York City's elderly population. Medications commonly prescribed for these conditions were reviewed, with a focus on their placement within the Medicare Formulary Tier system and associated costs. The analysis highlighted substantial variations in cost and tier placement, affecting patient affordability and adherence. For example, Alzheimer's medications like galantamine and rivastigmine were found in higher tiers, leading to increased out-of-pocket expenses, while COPD treatments such as Symbicort and Trelegy Ellipta, although in preferred tiers, still imposed significant financial burdens. Rheumatoid arthritis drugs showed a wide cost range, with Humira in Tier 5 presenting the highest financial challenge. Similarly, ischemic heart disease and type 2 diabetes medications varied in affordability, with drugs like Eliquis and Steglatro positioned in higher tiers, significantly impacting patient costs and potential treatment adherence. Conclusion: Elderly patients in the United States, especially those dealing with chronic conditions are facing a substantial financial strain due to the increasing prices of prescription medications. Even with recent initiatives like the Inflation Reduction Act aimed at lowering expenses, the financial burden persists, causing issues with treatment adherence and negative health results. The results highlight the pressing requirement for more effective policy actions that support price transparency, promote the utilization of cost-effective generics, and deter the unwarranted classification of generic drugs in higher formulary tiers. It is crucial to handle these problems to guarantee fair access to medications for all elderly individuals, specifically those who qualify for both Medicare and Medicaid.},
}

@article {pmid42253437,
year = {2026},
author = {Harel, M and Leibovici, A and Itzhaki, N and Ravona-Springer, R and Moshier, E and Doniger, GM and Gottlieb, A and Bahat, Y and Bendlin, BB and Zeilig, G and Plotnik, M and Beeri, MS and Livny, A},
title = {Virtual reality-based cognitive-motor training in middle-aged adults at high Alzheimer's disease risk improves frontal cortex cerebral blood flow: A randomized controlled trial.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {2},
pages = {e70265},
pmid = {42253437},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) pathological processes begin decades before symptom onset. Early intervention in high-risk populations may be crucial for prevention. We investigated the effect of an intervention utilizing virtual reality (VR) cognitive-motor training on cerebral blood flow (CBF) and cognitive functioning in middle-aged adults at high AD risk due to parental history.

METHODS: In this randomized controlled trial, participants (n = 79) were randomly assigned to: VR cognitive-motor training while walking on a treadmill (VR+T, n = 24, treatment); VR cognitive training without treadmill (VR-T, n = 21, active control); treadmill walking while watching documentaries (TV+T, n = 20, active control); or no intervention (n = 14, passive control). Training consisted of 45-min sessions, twice weekly, for 12 weeks. CBF was measured at resting state using arterial spin labeling (ASL) at baseline, 3-month, and 6-month follow-up. Cognition was assessed using a comprehensive neuropsychological battery. We applied the intent-to-treat approach.

RESULTS: All groups improved in executive functions and memory over time (all p-values < 0.05), with no consistent between-group differences at follow-up. CBF of the VR+T group significantly increased at 3 months in the superior (p = 0.013, middle (p = 0.014), and inferior (p = 0.003) frontal gyri compared to the passive control group, which showed a decline in CBF over the same period. No significant differences in frontal CBF change were observed between VR+T and the TV+T active control group. This increase was sustained for 6 months in the superior (p = 0.035) and middle (p = 0.028) frontal gyri. In contrast, in the middle temporal gyrus, the VR+T group had lower CBF at 3 months, compared to the VR-T (p = 0.033) and to the passive control groups (p = 0.004).

DISCUSSION: Cognitive-motor VR training increased CBF in frontal regions susceptible to early AD-related changes in middle-aged adults at high AD risk. This intervention shows promise as a preventive approach and may be suitable for implementation as a home-based program for individuals at high risk.},
}

@article {pmid42255952,
year = {2026},
author = {Sonson, M and Yadollahikales, G and Flores, A and Lasner, I and Lee, S and Tan, Z and Quach, C and Kremen, S},
title = {From clinical trial to clinical experience: Lecanemab therapy in a real-world case series.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70365},
pmid = {42255952},
issn = {2352-8729},
abstract = {The approval of anti-amyloid therapies has expanded therapeutic options for patients with Alzheimer's disease (AD), but the pivotal trials that proved their efficacy restrict their applicability to a selected patient population. We describe a case series of seven patients with biomarker-confirmed AD pathology evaluated in an academic memory clinic and treated with lecanemab whose characteristics would have disqualified them from trial participation. Patient histories and outcomes are presented, accompanied by description of the clinical team's reasoning and application of published Appropriate Use Recommendations for each case. Overall, lecanemab was largely well tolerated, with no unexpected safety concerns and amyloid-related imaging abnormality rates comparable to trial data. Clinically, most patients remained stable over the treatment period, though some continued to decline. This series highlights the challenges and considerations in applying disease-modifying therapies beyond trial populations, emphasizing the need for real-world data to guide treatment in diverse AD presentations.},
}

@article {pmid42255953,
year = {2026},
author = {Wallace, A and Zhou, O and Hoang, MN and Porter, G and Padilla, C and Marshall, C},
title = {Lecanemab and amyloid-related imaging abnormalities: Real-world data from a single center experience.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70377},
pmid = {42255953},
issn = {2352-8729},
abstract = {INTRODUCTION: Lecanemab has demonstrated both safety and efficacy in clinical trials; however, routine clinical data are sparse. We contribute to the growing body of real-world safety data, with a special focus on amyloid-related imaging abnormalities (ARIA).

METHODS: We conducted a retrospective chart review of 146 patients treated with lecanemab according to appropriate-use recommendations at a specialty memory center clinic.

RESULTS: Real-world safety and efficacy data closely resemble published data in the Clarity-AD trial. Thirty-three patients (23%) discontinued treatment; all remaining patients completed at least 12 months of treatment. We observed a positive trend toward increasing ARIA edema/effusion (ARIA-E) with increasing mean arterial pressure and a mean amyloid clearance of -90.6 at 18 months.

DISCUSSION: When used according to appropriate-use recommendations, lecanemab is as safe as reported in the Clarity-AD trial. Further investigation into real-world data is necessary for a more complete evaluation of lecanemab's safety and efficacy.},
}

@article {pmid42248800,
year = {2026},
author = {Miguel, ACC and Martins-Teixeira, L and Aliberti, MJR and Brucki, SMD and Caramelli, P and Laks, J and Nitrini, R and Rebello Pinho, PJDM and Suemoto, CK and Barbosa, MG and Ferri, CP},
title = {Bridging the gap: estimates of undetected dementia in Brazil.},
journal = {Age and ageing},
volume = {55},
number = {6},
pages = {},
doi = {10.1093/ageing/afag163},
pmid = {42248800},
issn = {1468-2834},
mesh = {Humans ; Brazil/epidemiology ; Male ; Female ; *Dementia/epidemiology/diagnosis ; Prevalence ; *COVID-19/epidemiology ; Aged, 80 and over ; Aged ; Middle Aged ; Alzheimer Disease/epidemiology/diagnosis ; Cholinesterase Inhibitors/therapeutic use ; SARS-CoV-2 ; },
abstract = {OBJECTIVE: To estimate the proportion of dementia underdiagnosis in Brazil and assess variations by age, sex and macro-economic regions.

METHODS: Diagnosed dementia cases were estimated using Brazilian Unified Health System (SUS) data on prescriptions for acetylcholinesterase inhibitors (AChEIs), as a proxy for recognised Alzheimer's disease (AD) cases. Estimates were adjusted for the proportion of AD among all dementias, treatment coverage and disease stages. Expected dementia prevalence was derived from national estimates. Underdiagnosis was calculated by comparing diagnosed to expected cases, stratified by sex, age group and region. Uncertainty interval (UI) bounds were calculated applying ±1 SD of the mean Delphi consensus prevalence for each stratum. Estimates were conducted for 2024 and repeated for 2019 and 2022 for pre- and post-COVID-19 pandemic comparison.

RESULTS: The overall proportion of dementia underdiagnosis among individuals aged ≥60 in 2024 was 84.3% (UI: 81.5-86.4). Proportions were higher among men (86.3%, UI: 83.5-88.2) than women (83.0%, UI: 79.9-85.2). Underdiagnosis peaked at 93.2% (UI: 92.3-93.7) in the 60-64-year age group, declined to 78.9% (UI: 78.1-79.6) among 85-89 years, then rose to 86.2% (UI: 85.7-86.7) among those ≥90 years. Proportions were highest in the poorest regions (North, Northeast and Central-West: 93.0%, UI: 91.4-94.1) and lowest in the richest (South and Southeast: 78.3%, UI: 74.3-81.2). Pre-pandemic (2019) underdiagnosis was slightly lower (81.6%, UI: 78.3-84.0) than in 2022 (84.9%, UI: 82.2-86.9) and 2024.

CONCLUSION: Dementia underdiagnosis in Brazil is high and unequally distributed, worsening after the COVID-19 pandemic. Expanding diagnostic access is critical to address disparities and improve care.},
}

Humans
Brazil/epidemiology
Male
Female
*Dementia/epidemiology/diagnosis
Prevalence
*COVID-19/epidemiology
Aged, 80 and over
Aged
Middle Aged
Alzheimer Disease/epidemiology/diagnosis
Cholinesterase Inhibitors/therapeutic use
SARS-CoV-2